Two Multicenter, Randomized Studies of
`the Efficacy and Safety of Cyclosporine
`Ophthalmic Emulsion in Moderate to Severe
`Dry Eye Disease
`
`Kenneth Sall, MD,' Onex Dara Stevenson, MD/ Thomas K. Mundmf, MD,3 Brenda L. Reis, PhD4 and
`th~ CsA Phase 3 Study Group
`
`Objective: To compare the efficacy and safety of cyclosporin A ([GsA] 0.05% and 0.1 % ophthalmic
`er.1ulsions) 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
`trAatment group).
`Methods: Two identical clinical trials; patients were treated twice daily with either GsA, 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
`w.thout anesthesia), tear break-up time, Ocular Surface Disease Index (OSDI), facial expression, patient subjec(cid:173)
`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,
`in~raocular pressure, biomicroscopy, and blood trough GsA concentrations.
`Results: Treatment with GsA, 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). GsA 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
`trPatment). There was no dose-response effect. Both GsA treatments exhibited an excellent safety profile, and
`there were no significant topical or systemic adverse safety findings.
`Conclusions: The novel ophthal mic formulations GsA 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 GsA 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(cid:173)
`ea~e. 1- 4 there is currently no therapeutic treatment for this
`condition. Individuals plagued by the discomfort , burning,
`in itation, photophobia, and other symptoms of dry eye
`disease may also have blurred vision, gradual contact lens
`in,oJerance, and the inability to produce emotional tears, as
`
`Manuscript no. 99316.
`
`Ot.ginally received June 16, 1999.
`Accepted: December 8, 1999.
`1 ~all Eye Surgery Center, Bellflower, California.
`2 Stevenson Medical and Surgical Eye Center, New Orleans, Louisiana.
`3 Charlotte, North Carolina.
`4 ~->llergan, Inc., Irvine. California.
`Reprint requests to: Linda Lewis, 575 Anton Blvd, Suite 900, Costa Mesa,
`CA 92626.
`Su;>ported by a grant from Allergan Inc.
`Dr. Reis is an employee of Allergan, Inc . None of the other authors has a
`fir •. mcial interest in any of the products mentioned in this paper.
`
`well as an increased risk of ocular stuface damage and
`ocular infection.5- 9 Yet, at this time, the only treatments
`available are paUiative in nature, consisting of lubricating
`eyedrops or puncta] occlusion procedures that attempt to
`supplement the patient's natural tears or improve the resi(cid:173)
`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(cid:173)
`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(cid:173)
`mediated inflammatory process affecting both the lacrimal
`gland and the ocular surface.2·10- 14 Tllis hypothesis is fur(cid:173)
`18 and human 20
`2
`ther supported by results from anima1 15-
`-
`t
`(Foulks et al, Invest Ophthalmol Vis Sci 1996;37:S646;
`Helms et a!, 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
`Pu'1lished by Elsevier Science Inc.
`
`ISSN 0 161 -6420/00/$-sce front 1mllter
`Pll S0161 ·6420(99)00176· 1
`
`631
`
`APOTEX 1004, pg. 1
`
`

`

`Ophthalmology Volume 107, Number 4, April 2000
`
`Turner et al, Invest Ophthalmol Vis Sci l999;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(cid:173)
`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(cid:173)
`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 Sjogren's syndrome. In addition, specialized assays
`were performed on conjunctival biopsy specimens from a
`subset of patients to investigate the levels of several inflam(cid:173)
`matory markers and the density of conjunctival goblet cells
`before and after treatment. The results of these specialized
`studies will be reported separately; prelinunary reports have
`been presented (Kunert et al, Invest Ophthalmol Vis Sci
`1999;40[4]:S77 1; Turner et a!, Invest Ophthalmol Vis Sci
`1999;40[ 4]:S558).
`
`Materials and Methods
`
`Study D esign
`
`Two identical multicenter, randomized, double-masked, parallel(cid:173)
`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 com mon 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(cid:173)
`tions, Sponsor and Investigator Obligations, Informed Consent
`Regulations, and the Declaration of Helsinki. Pote ntial patients
`signed a prescreening informed consent. A second written in(cid:173)
`formed consent was obtained from all patients before actual en(cid:173)
`rollment, and a separate informed consent was obtained for the
`subset of patients who participated in the pharmacokinetic evalu(cid:173)
`ations.
`Patients. Adult patients of either sex were eligible for partic(cid:173)
`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"): (I)
`Schirmer test without anesthesia of :S 5 mm/5 min in at least one
`eye (if Schinner test without anesthesia of = 0 nun/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 ~ +5 in the same eye where corneal staining was ~
`+ 2; (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(cid:173)
`cluded artificial tear drops, gels and ointments, sympathomimetic
`
`agents, parasympathomimetic agents, and puncta! occlusion. Eli(cid:173)
`gible patients were enrolled if they were deemed capable of
`following the study protocol and considered likely to complek the
`treatment period and return for all scheduled visi ts; if they had
`normal lid position and closure, and a best-cmTected ETDRS
`visual acuity score of +0.7 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 preser re or
`history of any systemic or ocular disorder or condition (including
`ocular surgery, trauma, and disease) that could possibly int~"rfere
`with the interpretation of the study results; current or recent use of
`topical ophthalmic or systemic medications that could affect 1 dry
`eye condition; known hypersensitivity to any component of the
`study or procedural medications; required contact lens wear L.Jring
`the study; recent (within I month) or anticipated use of temporary
`punctal plugs dllling the study; permanent occlusion of lat dmal
`puncta within 3 months of the study; or if they were pregnant,
`lactating, or planning a pregnancy. Patients were also excluJed 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 c" IIS or
`scarring. Any patient who no longer met the criteria for moderate
`to severe dry eye (as defined previously) after completir g the
`2-week run-in phase was excluded from enrollment in the treat(cid:173)
`ment phase of the study.
`Patients could be discontinued before the completion of the
`study because of adverse events, pregnancy, protocol viol..tions,
`lack of efficacy, or administrative or personal reasons.
`Study M edications. CsA, 0.05% and 0. 1 %, ophthalmic emul(cid:173)
`sions and the vehicle of CsA ophthalmic emulsion were the study
`medications, with indi vidually packaged preservative-free ani ficial
`tears (REFRESH Lubricant Eye Drops, Allergan, Inc.) provided as
`an adjunctive treatment to be used as frequently as needeu. The
`doses of CsA used were based on the results of an earlier dose(cid:173)
`ranging study? 1 Both the CsA emulsions and vehicle were sterile,
`nonpreserved castor oil ill water emulsions whose precise rormu(cid:173)
`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 dis~retion
`of the investigator and noted on the case report form. If the
`medication would not interfere with the response to stud) medi(cid:173)
`cation, the patient was kept in the study. During the study, all
`concomitant medication treatment regimens were kept as constant
`as pennitted by accepted medical practice. Systemic and topical
`ophthalmic medications that could interfere with the response to
`study medications or the interpretation of the study resul•~ were
`prohibited during the study. This included cyclospori ne, other
`immunomodulatory agents, general anesthetics, antihist~ "llines,
`cholinergic agents, antimuscarinics, 13-blocking agents, tricyclic
`antidepressants, phenothiazines, topical ophthalmic steroid• estro(cid:173)
`gen-progesterone (or other estrogen derivatives), or any topical
`ocular medications other than the assigned study medicat;J n and
`assigned artificial tears.
`Study Protocol. During the 2-week run-in phase, all !Jatients
`were instructed to use the assigned artificial tears only (as needed).
`During the treatment phase, patients were instructed to iJ1still I
`drop of study medication twice daily in each eye for 6 Plonths;
`once on waking in the morning and once at bedtime. Patients were
`allowed to use the assigned artificial tears as needed up t0 mo~th
`4. To avoid dilution of the study medication, patients were Ill"
`structed not to use artificial tears within 30 minutes before ' rafter
`use of the study medication. To mini mize the habitual conco~it~n:
`use of artificial tears, patients were asked to stop using a uficW
`
`632
`
`APOTEX 1004, pg. 2
`
`

`

`r
`
`Salt et al · CsA in Dry Eye Disease
`
`tt.li"S I week before thei r month 4 study visit. At th is visit, patie nts
`were encouraged to use arti fi cial tears less than eight times a day
`fLr the rest of the study period.
`During the treatment phase , patients returned fo r evaluation
`atrer I, 3, 4, and 6 months of treatment.
`
`Outcome Measures
`Etficacy. The objecti ve signs monitored were corneal and inter(cid:173)
`p~lpebral conjunctival staini ng, Schinner tear test (with and with(cid:173)
`out anesthes ia), and tear break-up time. The subjective endpoints
`us:!d were the OSDI, the facial expression subjective rating scale,
`symptoms of dry eye, investigator's evaluation of glo bal response
`to treatment, treatment success, and artificial tears use. A ll these
`variables were evaluated at baseline and at each study visit, except
`fo, 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, mo nth 3, and month 6.
`For corneal fluorescei n staini ng, the entire cornea was exam(cid:173)
`ined using slit-lamp evaluation with a yellow barrier filter and
`co'1alt blue illuminatio n. 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(cid:173)
`jlll ctival staining was evaluated mo re than 30 seconds, but less
`than 2 minutes, later. Using white lig ht of moderate intensity, the
`inh.:rpalpebral regions of the temporal and nasal conju ncti va were
`graded using the same Oxford Scheme. The sum of corneal and
`intc:rpalpebral stain ing was therefore on a 0 to 15 point scale. On
`all scales, a negative change fro m baseline indicated an improve(cid:173)
`ment.
`The Schirmer tear test was petformed both with and without
`anesthesia and graded on a 5-point scale as follows: I ( < 3 mm/5
`mi P), 2 (3-6 mm/5 min), 3 (7-10 mm/5 min), 4 ( 11- 14 mm/5
`min), and 5 (> 14 mm/5 min) usi ng the worse eye. A positive
`ch~nge fro m baseline indicated improvement. Categori zed values
`were used to reduce overall within-patient var iability known to
`ocLur for Schirmer wetting scores. T he categories were chosen a
`priori on the bas is of cutoff points suggested by a review of the
`meJ ical literature and consultation with clinical investigators.
`T ime until random location tear break-up between bl inks was
`me,1sured only up to 10 seconds and recorded only if the value was
`less than l 0 seconds.
`fhe OSDI q uestio nnaire was used to evaluate the impact of a
`patiP-nt's dry eye disease on vision-related functioning.22 .It con(cid:173)
`sisted of 12 questions that were each rated from 0 = none of the
`timr to 4 = all of the time. An overall score was calculated by
`dividing the sum of the responses for all questions answered by the
`tota' possible score. Thus, overall scores ranged from 0 = no
`disability to I = complete di sability. A negative change from
`basdine indicated an improvement in vision-related fu nctioning.
`The S ubjective Facial E xpression Rating Scale23 consisted of
`nim. facia l schematics ranging from I (the happiest face) to 9 (the
`unhappiest face) analyzed in five grades from 1 (pictures I and 2)
`to 5 (pictures 8 and 9). A negative change from baseline indicated
`an improvement.
`~ymptoms of ocular discomfort, such as sti ngi ng/burning, itch(cid:173)
`ing. sandiness/grittiness, blurred vision, dryness, light sensitivity,
`pai n or soreness, were graded using a 5-point scale ranging from
`0 ==- do not have this symptom to +4 = always notice this
`symptom). A negative change from baseline indicated an improve(cid:173)
`mer t.
`The investigator completed a global evaluation of the overall
`effe ·t of the study medication re lative to the qualification visi t
`
`L
`
`usi ng a 7-point scale in wh ich 0 = completely c leared, I = =90%
`improvement, 2 = =75% improvement, 3 = =50% improvement,
`4 = =25% i mprovement, 5 = condi tio n unchanged, and 6 =
`condition worsened. Treatment success was defined as a global
`evaluation of ""90% improvement or better.
`Patient use of concomitant artificial tears was a lso moni tored.
`At each study visi t, patients were q ueried about the average num(cid:173)
`ber of times they used m1ificial tears each day during the past week
`and the number of days d uring the past week when they did not use
`any arti ficial tears .
`Safety. T he primary safety variable monitored was the occur(cid:173)
`rence of adverse events. T he severity of each adverse event ob(cid:173)
`served was rated from mild (awareness of sign or symptom, but
`easily tole rated) to severe (incapaci tating with inability to work or
`do usual activity). The relationship of the event to the study
`medication was assessed by the investigator as none, unl ikely,
`possible, probable, or definite.
`Other safety variables monitored included best-corrected visual
`acuity (using the ETDRS chat1), intraocular pressure (using Gold(cid:173)
`man applanati on tonometry), and biomicroscopy (using slit-lamp
`examination without pupil di lation). Pharmacokinetic testing was
`al so done on a subset of patients to determine blood trough CsA
`concentrations d uring treatment.
`Safety variables were evaluated at base line and at all study
`visits, except for intraocular pressure, which was o nly evaluated at
`baseline and month 6, and CsA blood le vels, which were evaluated
`at baseline and months I and 6.
`
`Other Measures
`
`Blood was collected from all patients for autoantibody testi ng to
`aid in the prospective identification of individuals with Sjogren's
`syndrome. Frozen samples were sent to a central laborato rY, (Co(cid:173)
`vance Central Laboratories Inc, Indianapolis, lN) for log in and
`inventory before shipment to the Scripps Reference Laboratory
`(San Diego, CA) for the actual tests. Blood samples were evalu(cid:173)
`ated for the presence of antinuclear antibodies, rheumatoid factor,
`and class SS-A and class SS-B Sjogren's antibodies.
`Blood was also collected from a subset of patients for deter(cid:173)
`minatio n of mean blood CsA trough concentration. Frozen samples
`were sent to the sponsor (A IIergan, Inc.) for analysis, under Good
`Laboratory Practices regulations, using liquid chromatography(cid:173)
`mass spectrometry mass/mass spectrometry (LC-MS/MS) with a
`quantitation limit of 0. 1 ng/ml.
`
`Statistical M ethods
`
`A ll analyses presented in this report were conducted on the intent(cid:173)
`to-treat patient population (all patients randomi zed). A last-obser(cid:173)
`vation carried-forward method was used to input missing data,
`although baseline data (before study treatment) were not canied
`fo rward. 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 tbe worse sum of corneal and
`interpalpebral conjunctival staini ng. If both eyes were comparable,
`the n 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 o n 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 OS DI 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 (ANOY A), with
`
`633
`
`APOTEX 1004, pg. 3
`
`

`

`Ophthalmology Volume 107, Number 4, April 2000
`
`Table l. Patient Disposition
`
`Enrolled
`Completed
`Discontinued
`Lack of efficacy
`Adverse events
`Lost to follow-up
`Personal reasons
`Protocol or enrollment violations*
`O thert
`
`CsA 0.05%
`
`293
`235 (80.2%)
`
`I (0.3%)
`19 (6.5%)
`4 ( 1.4%)
`9(3.1%)
`19(6.5%)
`6(2.0%)
`
`CsA 0.1 o/o
`
`292
`218 (74.7%)
`
`3 ( l.O%)
`29 (9.9%)
`3 ( 1.0%)
`14 (4.8%}
`21 (7.2%)
`4 (1.4%)
`
`292
`218 (74.7%)
`
`3 l l.O%)
`13 14.5%)
`11 (3.8%)
`9 0.1%)
`30 \ 10.3%)
`8 (2. 7%)
`
`CsA = cyclosporin A.
`* Protocol or enro llment violations included improper entry, non-compliance, and use of prohibited medications.
`t Other incl uded pregnancy, relocation, and removal from the study by t he sponsor.
`
`group and investigato r effects and interaction, was used to test for
`among-group differences in continuous variables. T he Cochran(cid:173)
`Mantei-Haenszel24 procedure with modi fied ridits, stratified by
`site, was used to test for differences in change fro m baseline
`among treatment groups in categorical vari ables and fo r among(cid:173)
`group di fferences in global response distributions. The paired 1 test
`method was used to analyze within-group changes from baseline in
`continuous variables, whereas the Wilcoxon sig ned rank test was
`used to analyze within-group changes fro m baseline in categorical
`variables.
`Statistical adjustment of P values for multiple comparisons
`have been addressed by use of the Fisher's least sign ificant differ(cid:173)
`ence protected tests to ensure that the experimental-wise error rate
`was 0.05. SpecificalJy, a pair wise comparison between either
`cyclosporine gro up and vehicle grou ps is considere d statistically
`significant if and o nly if ( I ) the overall compar iso n amo ng the
`three groups is significant at the 0.05 level, and (2) the pai r wise
`comparison between cyclosporine and vehicle is significant at the
`0.05 level. In addition, althoug h patients were evaluated at multi(cid:173)
`ple time points throughout the study, the pri mary endpoint is o n 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 fro m 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 5 0.05 was considered statis(cid:173)
`tically significant.
`
`Patient T reatment Assignment
`
`Qualified patients were randomly assigned to receive one of the
`three study medications in a I: I: I ratio using a block size of 3.
`Only a single randomization was used per tri al. 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 eqt• tl num(cid:173)
`bers in the three treatment groups and more than 76% (67 1/877)
`completed the study (Table I). The fi rst patient was enr )Jied in
`July L997 and the last patient completed the 6-month treatment
`period and evaluatio n in September 1998. Most of the patk.lts who
`exited the study prematurely did so as a result of protocol or
`enrollment violations, personal reasons, lost to follow-up, c~r other
`no ntreatment-re lated 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 % grouo, and 3
`of 292 (1.0%) in the vehicle group. Only 7.0% (6 1/877) were
`discontinued because of adverse events; 19 of 293 (6.5o/- ) 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 ,,re listed
`in Table 2. Overall, most of the patients were women (82%;
`7 15/877) and Caucasian (84%; 740/847). There were no statisti(cid:173)
`cally significant differences between the treatment groups in any of
`the demographic variables measured. The use of prior therapy, or
`the types of concomjtant medications used during the o•udy for
`other medical conditions, were similar among the treatment
`groups.
`Sjogren's syndrome was defined as the presence of ocular
`symptoms, oral symptoms, and a Schirmer test 5 5 mm, <.. well as
`the presence of at least one of the following autoant ibodi~s:
`antinuclear antibod ies, rheumatoid fac to r, and Sjogren's aL£ibod1es
`class SS-A and SS-B. Of the 877 enrolled patients, 270 (30.8%)
`were determined to have Sjogren' s syndrome on the basi~ of the~e
`criteria. The number of patients wi th Sjogren's syndrome identl·
`fied may underestimate the number in the study popul ation be·
`cause some patients left the studies without having auto1ntibo<lY
`data collected and therefore could not meet the criteria for
`Sjogren's syndrome.
`
`The study medicatio n was packaged, labeled, and m asked in a
`manner consistent with Good Manufac turing Practices for inves(cid:173)
`tigationa l supplies. Ide ntical unjt-dose vials were used to hold the
`study treatments, which were each of an identical milky color.
`
`Efficacy Analysis
`C orneal Staining. At baseline, the mean values for corw 1l sta~~
`ing in the different treatment groups ranged between 2.61 an~ 2. ·r(cid:173)
`(using the Oxford scale from 0 to 5), with no statisticallo sigOI
`
`634
`
`APOTEX 1004, pg. 4
`
`

`

`Sall et al · CsA in Dry Eye Disease
`
`Table 2. Patient Demograph ics
`
`CsA 0.05%
`(n = 293 )
`58.7:!: 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 = 292 )
`60. 1 ± 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%)
`
`Age (mean ± SD)
`Sn
`Male
`Female
`Race
`Caucasian
`African-American
`Asian
`Hispanic
`Other
`lrb color
`Blue
`drown
`G reen
`J lack
`Hazel
`.:>ther
`Sjogren's syndrome patients
`
`Cs '\ = cyclosporin A .
`
`1
`
`Vehicle
`(n = 292)
`59.9 :!: 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 ( l.O%)
`9 1 (31.2%)
`
`icnnt differences among the groups. There was a statistically
`significant improvement from baseline in corneal staining (de(cid:173)
`crease in mean score) within all treatment groups at all follow-up
`visits (P < 0.00 1). The improvement in corneal staining was
`sirn ificantly greater in both CsA groups than the vehicle group (P
`s 0.044) at month 4, and in the CsA 0.05% group at month 6 (P
`= 0.008). There was also a trend (P = 0.062) toward a sign ifi (cid:173)
`cantly greater improvement in the CsA 0.1 % group than the
`vedicle group at month 6 (Fig I).
`Conjunctival staining. At baseline, the mean values for tem(cid:173)
`po. a! 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
`ba~eline values for nasal
`interpalpebral conj unctival staining
`ranged between 2.42 and 2.45, with no statistically signi ficant
`differences among the groups. Statistically significant im prove(cid:173)
`ments from baseline were seen in both temporal and nasal con(cid:173)
`jut t:tival staining within all study groups at all follow-up visits
`(P < 0.00 I), but there were no statistically significant among(cid:173)
`grc. up differences.
`
`the mean categorized
`Schirmer T ear Test. At baseline,
`Schirmer values (obtained with anesthesia) in the different treat(cid:173)
`ment groups ranged between 1.94 and 2.1 1 (on a scale from 0 to
`5 with 1 < 3 mm/5 min, 2 = 3-6 mm/5 min, 3 = 7-10 mm/5 min,
`4 = I 1-14 mm/5 min, and 5 > 14mm/S min), with no statistically
`significant differences among the groups. At month 3, there was a
`sign ificant worsening with the veh ic le group (P = 0.014) and a
`significant difference <m1ong the treatment groups, with the CsA
`0.05% group significantly greater than the vehicle group (P =
`0.009). At month 6, there was a statistically significant improve(cid:173)
`ment from baseline within both CsA groups. Moreover, the
`changes in Sch irmer values in each of the CsA groups was signif(cid:173)
`icantly better than in the vehicle group (P < -0.007; Fig 2).
`SchiJmer tear tests were also conducted without anesthesia. At
`baseline, the mean categorized Schirmer values (obtai ned 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
`
`Change From Baseline in Categorized Schirmer Values
`Measured With Anesthesia
`I• CsA 0.05% !II CsA 0.1% o Vehicle
`-
`-
`
`Change From Baseline in Corneal Staining
`
`Month 1
`
`Month 3
`
`Month 4
`
`Month 6
`
`·
`OG l
`0.5
`
`0.4
`
`0.3 •
`
`.0.1 -
`
`.().2
`
`Change .0.4
`
`'"
`Staining .0.5 ~
`Srore
`.0 .6
`
`1
`
`·0.7
`
`.O.B
`
`.0.9
`_
`1
`
`"
`
`• P !0. .05 compared to vehicle
`1 P = .62 compared to vehicle
`l• csA0.05%~CsA0.1%0Vehicle :
`
`Figure I. Change from baseline in corneal staining. Mean value ±
`stm .dard error. G raded on a scale from 0 to 5.
`
`Change 0.2.;
`
`Sch1t~mer o. 1
`o -l-- '- -ln-r..nnr - - , -- - -
`
`Score
`
`.0.1
`
`.0.2
`
`-0.3
`
`-0.4
`
`• P !0. .05 compared to vehicle
`
`Month 3
`
`Month 6
`
`Figure 2. Chmlgc from baseline in categorized Schirmer values (measured
`with anesthesia). Mean value ± 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.
`
`635
`
`APOTEX 1004, pg. 5
`
`

`

`Ophthalmology Volume 107, Number 4 , April 2000
`
`Change From Baseline in Blurred Vision
`
`Monlh 1
`
`Monlh 3
`
`Monlh4
`
`Monlh 6
`
`Change From Baseline In Average Dally Use of Ar licial
`Tears
`
`Monlh 1
`
`Monlh3
`
`Monlh 4
`
`MonL. 6
`
`0
`
`.0.1
`
`.0.2
`
`Change -o.3 •
`In
`Mean
`Score
`
`.0.4
`
`..0.5 -t
`
`·0.6
`
`·0.7
`
`• p .s. .05 compared 10 vehicle
`r.CsA o.05% I?'.ICsA 0.1% ovetiieie
`
`Change
`In
`Units per
`Day
`
`0
`
`.0.1
`
`.0.2
`
`·0.3
`
`·0.4 -
`
`·0.5 -
`
`-o.6 .J
`
`• P .s. .05 compared 10 vehicle
`
`I• CsA0.05% E'JC;;A0:1o/, OVehlcle
`
`Figure 3. Change from baseline in blurred vision. Mean value ::!:: sta ndard
`e rror. Graded on a scale from 0 to 4.
`
`Figure 4. Change from baseline in assigned lubricating cyedrop u• Mean
`value ::!:: 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(cid:173)
`ferences.
`Symptoms of Dry Eye D isease. 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 stati sticall y significan t within both CsA groups at all fol(cid:173)
`low-up visits (P ::;; 0.0 12) but only at month 6 within the vehicle
`group (P = 0.039). Moreover, the improvement in blurred vision
`was significantl y greater in the CsA 0.05% group than the vehicle
`group at all follow-up visits (P :S 0.0 14; 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 :S 0.038).
`Statistically significant improvements from baseline were seen in
`photophobia within both CsA groups at all follow-up visits (P :S
`0.028) and within the vehicle group at months 3. 4. and 6 (P :S
`0.023). Statistically significant improvements from baseline were
`also seen in buming and stinging within both CsA groups at
`months 4 and 6 (P :S 0.024) and within the vehicle group at
`months 3, 4, and 6 (P :S 0.019). There was also a statistically
`significant improvement from baseli