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. Mundmf, MD, 3 Brenda L. Reis, PhD4 and
`th~ CsA Phase 3 Study Group
`
`Objective: To compare the efficacy and safety of cyclosporin A ([CsA] 0.05% and 0.1 % ophthalmic
`e1 .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 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
`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 CsA concentrations.
`Results: Treatment with CsA, 0.05% or 0.1%, gave significantly (P :S; 0.05) greater improvements than
`vr:.hicle 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
`trPatment). 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.
`
`D~,;spite 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 discomf01t, burning,
`irritation, photophobia, and other symptoms of dry eye
`disease may also have blurred vision, gradual contact lens
`in,olerance, and the inability to produce emotional tears, as
`
`Manuscript no. 993 16.
`
`O ~oginally received June 16, 1999.
`Accepted: December 8, 1999.
`1 ~all Eye Surgery Center, Bellflower, California.
`2 ~Ievenson Medical and Surgical Eye Center, New Orleans, Louisiana.
`3 Charlotte, North Carolina.
`4 h llergan, Inc., Irvine, California.
`Repri nt 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, lnc. 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 swf ace damage and
`ocular infection. 5- 9 Yet, at this time, the only treatments
`available are palliative 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 botl1 the lacrimal
`14 Tllis hypothesis is fur(cid:173)
`gland and the ocular surface.2• 10 -
`18 and human 20
`2 1
`ther supported by results from ani mal 15
`-
`-
`(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):877 1;
`
`© 2000 by the Ame rican Academy of Ophthalmology
`Pu'1lished by Elsevier Science Inc.
`
`ISSN 0 161·6420/00/$-sce front matter
`PH SOI61 -6420(99)00176-1
`
`631
`
` EXHIBIT 1007
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`Sall et al · CsA in Dry Eye Disease
`
`ttJJS 1 week before their month 4 study visit. At this visit, patients
`were encouraged to use artificial tears less than eight times a clay
`fa the rest of the study period.
`During the treatment phase, patients returned for evaluation
`al£er I, 3, 4, and 6 months of treatment.
`
`Outcome Measures
`Etficacy. The objective signs monitored were corneal and inter(cid:173)
`p~lpebral conjunctival staining, Schirmer tear test (with and with(cid:173)
`out anesthesia), 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 g lobal response
`to treatment, treatment success, and artificial tears use. All these
`variables were evaluated at baseline and at each study visit, except
`fo, tear break-up time, which was not evaluated at the ! -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(cid:173)
`ined using slit-lamp evaluation with a yellow barrier fi lter and
`co11alt 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(cid:173)
`jlll ctival staining was evaluated more than 30 seconds, but less
`than 2 minutes, later. Using wh ite light of moderate intensity, the
`inh.:rpalpebral regions of the temporal and nasal conjunctiva were
`graded using the same Oxford Scheme. The sum of corneal and
`intt:rpalpebral staining was therefore on a 0 to 15 point scale. On
`all scales, a negative change from baseline indicated an improve(cid:173)
`ment.
`The Schirmer tear test was peif'ormed both with and without
`anesthesia and graded on a 5-point scale as follows: I (< 3 mm/5
`min), 2 (3- 6 mm/5 min), 3 (7-10 mm/5 min), 4 (1 1- 14 mm/5
`min), and 5 (> 14 mrn/5 min) using the worse eye. A positive
`chrnge from baseline indicated improvement. Categorized values
`were used to reduce overall withi n-patient variability known to
`oclur for Schirmer wetting scores. The categories were chosen a
`priori on the basis of cutoff points suggested by a review of the
`meJ ical literature and consultation with clinical investigators.
`Ti me until random location tear break-up between bl inks was
`measured only up to 10 seconds and recorded only if the value was
`less than I 0 seconds.
`The OSDI questionnaire 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
`tim•· to 4 = all of the time. An overall score was calculated by
`dividing the sum of the responses fo r all questions answered by the
`tota' possible score. Thus, overall scores ranged from 0 = no
`disability to 1 = complete disability. A negative change fro m
`basdine indicated an improvement in vision-related functioning.
`The Subjective Facial Expression Rating Scale23 consisted of
`nim. facial schematics ranging from I (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 basel ine indicated
`an improvement.
`~ymptoms of ocular discomfort, such as stinging/burning, itch(cid:173)
`ing. sandiness/grittiness, blurred vision, dryness, light sensitivity,
`pain or soreness, were graded using a 5-point scale ranging from
`0 = do not have th is symptom to +4 = always notice this
`symptom). A negative change from baseline indicated an improve(cid:173)
`mer !.
`The investigator completed a global evaluation of the overall
`effe t of the study medication relative to the qualification visit
`
`l
`
`using a 7-point scale in which 0 = completely cleared, I = = 90%
`improvement, 2 = =75% improvement, 3 = = 50% improvement,
`4 = =25% improvement, 5 = condition unchanged, and 6 =
`condition worsened. Treatment success was defined as a global
`evaluation of = 90% improvement or better.
`Patient use of concomi tant artific ial tears was also monitored.
`At each study visit, patients were queried about the average num(cid:173)
`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(cid:173)
`rence of adverse events. The severi ty of each adverse event ob(cid:173)
`served was rated from mi ld (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 mon itored included best-corrected visual
`acuity (using the ETDRS chart), intraocular pressure (usi ng Gold(cid:173)
`man applanation tonometry), and biom icroscopy (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 on ly evaluated at
`baseline and month 6, and CsA blood levels, which were evaluated
`at baseline and months I and 6.
`
`Other Measures
`
`Blood was collected from all patients for autoantibody testing to
`aid in the prospective identification of individuals with Sjogren's
`syndrome. Frozen samples were sent to a central laboratorx (Co(cid:173)
`vance Central Laboratories Inc, Indianapolis, IN) fo r log in and
`inventory before shipment to the Scripps Reference Laboratory
`(San D iego, 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)
`mination of mean blood CsA trough concentration. Frozen samples
`were sent to the sponsor (Ailergan, 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/m l.
`
`Statistical M ethods
`
`All analyses presented in this report were conducted on the intent(cid:173)
`to-treat patient popu lation (all patients random ized). A last-obser(cid:173)
`vation carried-forward method was used to input missing d ata,
`although baseline data (before study treatment) were not canied
`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 o n 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.
`Desc ripti ve s tatistics 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 (ANO Y A), with
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