ALCON 2020
`Apotex Corp. v. Alcon Research, Ltd.
`Case IPR2013-00428
`
`

`

`differences in the IOP»lowering ability of these medica»
`tions at 8 AM, the time of peak effect, and differences at
`other time points may have been confounded by baseline
`differences. The exception was a recent investigation23
`suggesting that bimatoprost may be more effective than
`latanoprost in reducing IOP levels. Less open to debate has
`been the relative frequency of several ocular adverse
`events, most notably ocular hyperemia, which may affect
`patient compliance and thus the overall effectiveness of
`the topical prostaglandin analogues. Compared to latano’
`prost, both bimatoprost and travoprost have been shown to
`have substantially higher rates of ocular side effects.14v22
`The present trial is the first to compare simultaneously the
`clinical outcomes associated with the use of latanoprost,
`bimatoprost, and travoprost.
`
`METHODS
`
`0 SETTING: This 12¢week, randomized, parallel’group,
`masked’evaluator study conducted at 45 sites
`in the
`United States compared the efficacy and safety of once
`daily administration of three commercially available pros;
`taglandin analogues:
`latanoprost 0.005%, bimatoprost
`0.03%, and travoprost 0.004% ophthalmic solutions. Reg;
`ulatory authorities at each study site reviewed and ap’
`proved the protocol in accordance with guidelines for the
`conduct of clinical research contained in the 1964 Decla’
`ration of Helsinki.
`
`0 PATIENTS: Patients were eligible for participation if
`they met the following inclusion criteria: age 2 18 years;
`bilateral or unilateral primary open’angle glaucoma, exfo’
`liative glaucoma, pigmentary glaucoma, or ocular hyper;
`tension (IOP 2 21 mm Hg at diagnosis); current or
`previous (within the past 6 months) monotherapy or dual
`therapy with a topical ocular hypotensive agent( s); best;
`corrected visual acuity equal to or better than 20/200; and
`ability to comply with the requirements of the study
`protocol. All patients provided signed informed consent
`prior to study enrollment.
`Exclusion criteria were known hypersensitivity to any
`component in the study medications; use of any medical
`tion known to affect IOP unless both patient and dosage
`were stable within the previous 3 months and no change in
`dosage was expected during the study; use of any investi’
`gational medications within 30 days of the screening visit;
`history of acute angle’closure or closed or slit open anterior
`chamber angle; argon laser trabeculoplasty or other ocular
`(globe) surgery within the previous 3 months or any
`previous filtering surgery (an unlasered or unfiltered eye
`could be enrolled as the study eye); ocular infection or
`inflammation within the previous 3 months; and preg’
`nancy, lactation, or inadequate contraception.
`
`0 TREATMENT PROTOCOL: A screening visit examina»
`tion for all patients (up to 1 month prior to the baseline
`visit) included a review of ocular and medical history, IOP
`measurement with a calibrated Goldmann applanation
`tonometer, Snellen visual acuity measurement, slit’lamp
`biomicroscopy, ophthalmoscopy, and visual field testing
`(automated perimetry)
`if not done within the past 12
`months. Patients deemed eligible for the study were re;
`moved from all ocular hypotensive therapy at this time.
`Required washout periods prior to the baseline visit were 5
`days for cholinergic agonists and carbonic anhydrase in;
`hibitors; 2 weeks for adrenergic agonists; and 4 weeks for
`B’adrenergic receptor antagonists and prostaglandin ana’
`logues. For all patients previously using B’adrenergic re;
`ceptor antagonists and prostaglandin analogues,
`IOP
`measurement was required as a safety check after 2 weeks
`of washout; observed IOP levels considered potentially
`hazardous resulted in patients being excluded from the
`study.
`Study visits occurred at baseline and after 2, 6, and 12
`weeks of therapy. At the baseline visit, which followed the
`washout period, masked evaluators performed three IOP
`measurements in each eye, alternating between eyes, and
`starting with the right eye at 8:00 AM, 12 noon, 4:00 PM,
`and 8:00 PM. The mean of these IOP measurements at each
`
`time point was used in statistical analyses. Either one or
`both eyes of a patient could be enrolled as study eyes. An
`eye was eligible if the mean IOP was 223 mm Hg at the
`8:00 AM baseline measurement. For patients having both
`eyes enrolled, the mean of the IOP readings in both eyes
`was used as the patient’s IOP in the analyses. In patients
`with bilateral disease with only one eye that met all
`eligibility criteria (study eye), the other eye also could be
`treated with study drug provided that no exclusion criteria
`existed for that eye. If both eyes met all eligibility criteria,
`both were enrolled as study eyes.
`Study medications were packaged in commercially avail,
`able labeled containers manufactured by Pharmacia Cor;
`poration (latanoprost), Allergan (bimatoprost), and Alcon
`Laboratories (travoprost). To preserve masking, each con;
`tainer was overpackaged in an opaque black vial and then
`sealed in a patient kit with tamper’evident strips; the name
`of the drug was not included on kit labels. A designated,
`unmasked coordinator (who did not perform any study
`evaluations or assessments) at each study center received
`randomization codes and prepackaged clinical supplies
`from Pharmacia Clinical Supply Logistics (Kalamazoo,
`Michigan, USA), and dispensed the medication kits. The
`coordinator was responsible for storing each medication kit
`according to its respective product package insert.
`Following the 8:00 PM baseline measurement, eligible
`patients were randomly assigned within each study center
`to one of three treatment groups in a 1:121 ratio: latanoi
`prost 0.005%, bimatoprost 0.03%, or travoprost 0.004%.
`One patient medication kit was dispensed to each eligible
`patient at the baseline visit and another at the week 6
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`FIGURE 1. Standard photographs used to assess grades of conjunctival hyperemia.
`
`visit; patients were instructed to return all study medica»
`tions at week 12 or at the final visit for those discontinuing
`the study early. Patients were reminded to change study
`medication bottles every 4 weeks. Each medication was to
`be instilled daily at 8:00 PM, and no other IOPrreducing
`therapy was permitted. Instillation of study medication
`began on the evening of the baseline visit. Physician
`investigators (hereafter called investigators) and evaluators
`remained masked to treatment
`throughout
`the study;
`patients were the only ones aware of their treatment
`assignments and were cautioned not to reveal the treat;
`ment assignment to masked study’site personnel. At weeks
`2, 6, and 12, investigators noted on the case report form
`whether or not masking had been maintained. The statis’
`tician also was masked until the database was closed,
`
`Intraocular pressure was measured at any time during the
`day at week 2 and at 8:00 AM, 12 noon, 4:00 PM, and 8:00
`PM at weeks 6 and 12 (or at time of earlier discontinuar
`
`tion), As at baseline, masked evaluators performed three
`IOP measurements in each eye, alternating between eyes,
`and starting with the right eye at each specified time point.
`At weeks 6 and 12, patients were questioned to ensure that
`the last eyedrop was administered the evening before the
`visit. The mean of the three IOP measures for each eye at
`each time point was used in statistical analyses.
`At baseline and weeks 6 and 12, an investigator masked
`to treatment completed a conjunctival hyperemia grading
`scale before the 8:00 AM IOP measurement; at week 2,
`
`grading was performed prior to tonometry. The presence
`and severity Of hyperemia were assessed by the method
`used in several phase 3 registration trialslo’12 Each eye was
`compared with standard photographs showing conjuncti’
`val hyperemia of grades 0,
`1, 2, and 3 (none, mild,
`moderate, and severe, respectively) (Figure 1); the scale
`included values of 0, 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0. In
`
`the same investigator asked pa;
`addition, at every visit,
`tients whether they or anyone else had noticed any redness
`in his or her eye(s) since the last visit and, if so, to what
`extent they were bothered by such redness. Extent of
`
`symptom was graded with the following responses: not at
`all, a small amount, a moderate amount, or a great amount.
`Investigators recorded patients’ responses,
`Throughout the study, any undesired medical occur;
`rence regardless of relationship to treatment was consid
`ered an adverse event and was monitored. Defined criteria
`
`were used to grade the intensity of each adverse event and
`to classify the event as serious or nonserious. Any adverse
`event considered serious, related to study medication and
`persistent, or any ocular adverse event present at the end
`of study treatment (week 12) resulted in patients being
`followed up for 2 weeks after the final visit. Followup of
`serious adverse events considered to be related to a study
`medication continued until events were resolved or
`deemed chronic or stable.
`
`. MAIN OUTCOME MEASURES AND ANALYSES: The
`
`Fisher least significant difference procedure was used to
`compare treatment groups.“ Continuous variables were
`tested for treatment group differences using onerway anal»
`ysis of variance (ANOVA) with treatment (latanoprost,
`bimatoprost, or travoprost) as the independent variable. If
`the overall treatment effect was not significant (P > .05),
`it was concluded that no difference existed between
`treatment means.
`If
`the overall
`treatment effect was
`
`significant (P S .05), pairwise comparisons of treatment
`means were performed using t tests, with the significance of
`each set at the .05 level.
`
`The primary efficacy outcome, mean change between
`baseline and week 12 in IOP measurements obtained at
`
`8:00 AM (time of peak drug effect), was analyzed using the
`above procedure, but with the analysis of covariance model
`(ANCOVA), with baseline IOP as the covariate and
`treatment and center as factors. If the overall treatment
`
`effect was significant, pairwise comparisons of treatment
`means were performed using contrasts. The 95% confi’
`dence interval (CI) of the difference in the mean change
`was calculated based on the ANCQVA model. This
`
`procedure also was applied to the secondary outcomes,
`
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`Randomized: 11:411
`
`
`
`
`
`
`Allocated t
`o biinaioprost:
`n: I 3 7
`Allocated to latanoprost:
`Allocated to travoprost:
`nnl 3 6
`11:1 3 8
`No postbase.ine assessment:
`
`11:1
`
`
`Included in ITT analyses:
`n: l 3 6
`
`Did not meet inclusion/
`exclusion criteria: 11:]
`
`Inadequate washout:
`11:3
`
`Nlissed IOP assessment
`at baseline: nu]
`
`Included in ITT analyses:
`[1:136
`
`Assigned wrong study
`medication: 11:]
`
`Did not meet inclusion/
`exclusion criteria: 11:1
`
`Inadequate washout: 1172
`
`Included in [TT analyses:
`11:! 3 8
`
`Assigned wrong study
`medication: 11:2
`
`Did not meet inclusion/
`exclusion criteria: n=l
`
`Early termination: 11756
`
`
`
`
`
`
`
`
`
`Early termination: na-o
`
`Early termination: 11:5
`
`
`Included in perxprotocol
`Included in per-protocol
`analyses: 11*126 analyses: 11:12 7
`
`
`
`
`Included in per-protocol
`analyses: 112129
`
`FIGURE 2. Flow diagram of patient disposition. IOP = intraocular pressure; ITT = intent—to—treat.
`
`mean change between baseline and week 12 in IOP
`measurements obtained at 12 noon, 4:00 PM, and 8:00 PM
`(time of trough), and in diurnal IOP, which was defined as
`the mean of IOP measurements at 8:00 AM, 12 noon, 4:00
`PM, and 8:00 PM. Within’treatment group IOP changes
`were tested with paired t tests. Categorical variables are
`presented in contingency tables with counts and percent;
`ages, and a Fisher exact test or chi’square test was used to
`test for treatment group differences. All statistical
`tests
`were two’tailed and were performed at the .05 significance
`level.
`
`Racial differences in treatment response also were ana’
`lyzed using the ANCOVA model, with change from
`baseline to week 12 in 8:00 AM IOP as the dependent
`(outcome) variable, baseline 8:00 AM IOP as the covariate,
`
`and treatment, center, race, and treatment’by’race inter;
`action as other factors. Race was categorized as Caucasian,
`black, and other for this analysis. A similar analysis was
`conducted on IOP change between baseline and week 12
`in 8:00 PM IOP.
`
`Separate and parallel efficacy analyses of both intent’to’
`treat (ITT) and per’protocol populations were conducted.
`All efficacy analyses were based on study eye(s). The ITT
`analyses included all randomized patients who had at least
`one valid IOP evaluation after beginning treatment with
`study medication. For ITT analyses, missing IOP measure;
`ments at week 12 were obtained by carrying forward the
`corresponding week 6 measurements. Diurnal IOP then
`
`was calculated based on available measurements. If no
`
`measurement was available,
`
`the diurnal measurement at
`
`the previous visit was carried forward. Missing values at
`week 6 were imputed using week 2 data. Although 2.1% of
`the 5,330 expected IOP observations were missing, per;
`protocol analyses that excluded patients who did not
`complete the study or who had major protocol violations
`also were conducted to confirm ITT results. Those analyses
`included all patients who completed the full course of
`treatment without a major violation of protocol guidelines;
`no missing data were imputed for the per’protocol analy’
`ses.
`
`Safety analyses included all randomized patients (safety
`population). The Medical Dictionary for Regulatory Ac;
`tivities (MedDRA) coding system was used to classify
`adverse events. Frequencies of ocular and systemic adverse
`events and numbers of patients affected were summarized
`by treatment group. Ocular adverse events and hyperemia
`events (MedDRA preferred terms: ocular hyperemia, red
`eye, conjunctival vascular disorder not otherwise specified,
`and conjunctivitis not elsewhere classified) also were
`summarized by maximum intensity. Masked investigators’
`and patients’ assessments of hyperemia were summarized by
`treatment and visit and were tested for treatment differ;
`
`ences. Each patient’s hyperemia score was calculated by
`taking the mean of the hyperemia scores of the patient’s
`treated eyes. Other safety variables, such as visual acuity,
`
`VOL. 135, No.5
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`
`
`- Latanoprost (112136)
`Birnatoprost (11:13 7)
`'l‘ravoprost (112138)
`
`l
`
`‘
`
`PercentageofPatients
`
`
`
`FIGURE 3. Frequencies of patients receiving intraocular pressure (IOP)—reducing medication at screening (intent—to—treat
`population). Some patients were taking dual therapy.
`
`Ocular Hypotensive Medications at Screening
`
`changes after treatment in the lid and slitalamp examina
`tion, and ophthalmoscopy results, also were tabulated.
`Before the study, it was determined that a sample of at
`least 113 patients capable of being evaluated per treatment
`group was required to detect a difference of 1.5 mm Hg in
`mean IOP reduction between the two treatment groups at
`a significance level of .05, with a power of .80 and
`assuming a standard deviation (SD) of 4.0 mm Hg. The
`plan was to include a minimum of 375 patients so as to
`allow for patient withdrawals.
`
`RESU LTS
`
`In all,
`. PATIENT DISPOSITION AND DEMOGRAPHICS:
`514 patients were screened; 1 patient was excluded at the
`week 2 safety check because of an elevated IOP. Following
`enrollment at baseline, 411 patients were randomized to
`three treatment groups: latanoprost (n = 136), bimato’
`prost (n = 137), and travoprost (n = 138) (Figure 2). One
`patient in the bimatoprost group received medication but
`had no postbaseline evaluation and was excluded from ITT
`
`analyses. The resulting ITT population comprised 410
`patients of whom 172 (42.0%) were male, 229 (55.9%)
`were Caucasian, and 125 (30.5%) were African American.
`Diagnoses included primary open’angle glaucoma in 309/
`410 (75.4%) patients, ocular hypertension in 95/410
`(23.2%) patients, and exfoliative or pigmentary glaucoma
`in 5/410 (1.2%) patients; 1 patient had none of the listed
`diagnoses. Study participants had a mean age of 65 years.
`At screening, the latanoprost, bimatoprost, and travoprost
`ITT groups had similar proportions of patients taking a
`prostaglandin analogue (52.9%, 49.6%, and 47.1%, respec’
`tively) (Figure 3), and those taking a prostaglandin had
`similar mean IOP levels (19.4 mm Hg, 19.6 mm Hg, and
`19.9 mm Hg, respectively) (Figure 4). Demographic and
`baseline characteristics were generally similar across treat,
`ment groups with no statistically significant differences
`found (Table 1). Overall, 98/136 (72.1%) of latanoprost;
`treated patients, 96/136 (70.6%) patients receiving bi;
`matoprost, and 79/138 (57.2%) of those treated with
`travoprost had both eyes as study eyes, and 400/410
`(97.6%) patients received assigned study medication in
`both eyes (one eye of which may not have been a study
`
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`
`
`
`
`Mean1.013(mmHg)
`
`26
`
`25
`24
`
`I Latanoprost (11:13.6)
`B imatoprost (11:13 7)
`I Travoprost (11:138)
`
`
`
`FIGURE 4. Mean intraocular pressure (IOP) at screening by TOP—reducing medication (intent—to—treat population). Some patients
`were taking dual therapy.
`
`
`Ocular Hypotensive Medications at Screening
`
`eye). Of the 393/411 patients (95.6%) who completed the
`study, the average exposure to study medication was 86
`days, including the baseline day.
`Unmasking occurred in 6 patients (latanoprost, n = 3;
`bimatoprost, n = 1; travoprost, n = 2); in 3 of these cases,
`the technician was unmasked but the investigator was not.
`In all, 28/410 (6.8%) patients (latanoprost, n = 10;
`bimatoprost, n = 9; travoprost, n = 9) included in lTT
`analyses were excluded from perrprotocol evaluations ow»
`ing to major protocol deviations, early termination from
`the study, or both (Figure 2). Demographic characteristics
`and efficacy results of primary and secondary endpoints
`were similar in lTT and pereprotocol populations.
`
`0 EFFICACY RESULTS: At baseline, mean IOP levels
`
`were similar across groups at each time point and for the
`diurnal measurement (Table 2; Figures 5 and 6). With
`regard to the primary efficacy variable, mean 8:00 AM IOP
`levels at baseline were 25.7 mm Hg in the latanoprost
`group, 25.7 mm Hg in the bimatoprost group, and 25.5 mm
`Hg in the travoprost group (P = .772). By week 12,
`significant (P < .001) reductions were observed in all three
`treatment groups. The estimated mean i SEM IOP
`reduction (ANCOVA) was 8.6 i 0.3 mm Hg for those
`treated with latanoprost, 8.7 i 0.3 mm Hg for bimat0e
`prostetreated patients, and 8.0 i 0.3 mm Hg for patients
`receiving travoprost
`(P = .128 for difference among
`groups). Adjusted differences (see Methods) in mean IOP
`
`reductions at 8:00 AM also showed equivalence among
`treatments when latanoprost was compared with either
`bimatoprost (latanoprost versus bimatoprost: —0.13 mm
`Hg; 95% Cl —0.84, 0.58) or with travoprost (latanoprost
`vs travoprost: 0.56 mm Hg; 95% Cl —0.15, 1.26) and
`when bimatoprost was compared with travoprost (bimat0e
`prost vs travoprost: 0.69 mm Hg; 95% Cl —0.02, 1.40).
`The distributions of changes in IOP levels for
`the
`primary efficacy variable for each treatment group are
`given in Figure 7. Inspection of the distributions reveals
`quite similar box plots. Subgroup analyses for each treat;
`ment group, stratified by previous use or nonuse of a
`prostaglandin analogue (Figure 8A) or by the occurrence
`or nonoccurrence of investigatorenoted hyperemia (Figure
`8B), similarly do not reveal differences.
`Results of per’protocol analyses of changes from baseline
`to week 12 in mean IOP levels at 8:00 AM generally were
`supportive of those of lTT evaluations, although the
`overall
`treatment difference was significant (P = .029,
`ANCOVA). Adjusted differences (see Methods) in mean
`IOP reductions at 8:00 AM showed comparability between
`latanoprost and either bimatoprost (—0.22 mm Hg; 95%
`Cl —0.94, 0.50) or travoprost
`(0.71 mm Hg; 95% Cl
`—0.01, 1.42), but
`IOP levels were reduced more in
`bimatoprostetreated than in travoprostetreated patients
`(0.93 mm Hg; 95% Cl 0.22, 1.65).
`Mean IOP levels at week 12 were similar across treat;
`
`ment groups at all time points (Figure 6). The lTT analyses
`
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`
`TABLE 1. Demographic Data (lntent-to—Treat Population)
`
`Latanoprost
`Bimatoprost
`Travoprost
`
`(n : 136)
`(n : 136)
`(n : 138)
`
`n (%)
`n (%)
`n (%)
`
`60 (44.1)
`
`52 (38.2)
`
`60 (43.5)
`
`65.9 (11.27)
`28—90
`
`64.4 (12.35)
`29—85
`
`65.6 (10.81)
`26—82
`
`72 (52.9) _
`40 (29.4)
`20 (14.7)
`4 (2.9)
`0
`
`33 (24.3)
`92 (67.6)
`5 (3.7)
`6 (4.4)
`0
`
`22 (16.2)
`12 (8.8)
`2 (1.5)
`100 (73.5)
`
`105 (77.2)
`1 (0.7)
`1 (0.7)
`29 (21 .3)
`0
`
`74 (54.4)
`45 (33.1)
`12 (8.8)
`3 (2.2)
`2 (1 .5)
`
`35 (25.7)
`88 (64.7)
`3 (2.2)
`7 (5.1)
`3 (2.2)
`
`17 (12.5)
`10 (7.4)
`2 (1 .5)
`107 (78.7)
`
`103 (75.7)
`1 (0.7)
`1 (0.7)
`31 (22.8)
`0
`
`83 (60.1)
`40 (29.0)
`13 (9.4)
`2 (1.4)
`0
`
`40 (29.0)
`82 (59.4)
`4 (2.9)
`9 (6.5)
`3 (2.2)
`
`25 (18.1)
`5 (3.6)
`0
`108 (78.3)
`
`101 (73.2)
`1 (0.7)
`0
`35 (25 .4)
`1 (0.7)
`
`Gender
`
`Male
`Age (year)
`Mean (SD)
`Range
`Ethnic origin
`_
`Caucasian
`African American
`Hispanic
`Asian
`Other
`Eye color
`Homogeneously blue, gray, or green
`Homogeneously brown
`Blue-brown/gray-brown
`Green-brown
`Yellow-brown
`Nevi or freckles (study eye[s])
`On iris
`On conjunctiva bulbi
`On both
`Not present
`Diagnosis (study eye[s])
`Primary open-angle glaucoma
`Pigmentary glaucoma
`Exfoliative glaucoma
`Ocular hypertension
`None of listed diagnoses
`Duration of condition (study eye[s])
`:6 months
`>6 to 36 months
`>36 to 120 months
`>120 months
`
`12 (8.8)
`44 (32 .4)
`55 (40.4)
`25 (18.4)
`50 (36.8)
`70 (51 .5)
`
`6 (4.4)
`35 (25.7)
`72 (52.9)
`23 (16.9)
`53 (39.0)
`66 (48.5)
`
`10 (7.2)
`47 (34.1)
`55 (39.9)
`26 (18.8)
`58 (42.0)
`63 (45.7)
`
`Family history of glaucoma/ocular hypertension
`Visual field—any glaucomatous defect (study eye[s])
`Baseline lOP-lowering medications*
`65 (47.1)
`68 (50.0)
`72 (52.9)
`Prostaglandin analogues
`55 (39.9)
`44 (32.4)
`43 (31.6)
`Carbonic anhydrase inhibitors
`37 (26.8)
`44 (32 .4)
`35 (25.7)
`B-Adrenergic receptor antagonists
`20 (14.5)
`19 (14.0)
`16 (11.8)
`Adrenergic receptor agonists
`5pm
`4am
`spn
`Combination therapies
`3 (2.2)
`3 (2.2)
`4 (2.9)
`Masked investigational drugs
`
`
`
`Cholinergic agonists 0 3 (2.2) 1 (0.7)
`
`IOP : intraocular pressure.
`*Some patients were receiving dual therapy at baseline.
`
`revealed no significant differences among treatment groups
`in adjusted mean IOP reductions from baseline to week 12
`at 12 noon, 4:00 PM, or 8:00 PM (P = .075, P = .057, and
`
`P = .100, respectively). Also, no significant difference
`existed across treatments in changes in mean diurnal IOP
`levels measured at week 12 (P = .125); distributions of
`
`diurnal IOP reductions from baseline to week 12 are shown
`
`in Figure 7.
`In an exploratory analysis, no racial differences in
`patients’ responses to the treatments were observed; how;
`ever,
`the study was not powered to detect subgroup
`differences based on race. The ANCOVA model, using
`
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`
`
`TABLE 2. lntraocular Pressure (IOP) and lOP Reduction From Baseline to Week 12: Unadjusted Mean 1‘ SD
`(lntent-to—Treat Population)
`
`IOP (mm Hg)
`IOP Reduction (mm Hg): Baseline to Week 12
`Latanoprost
`Bimatoprost
`Travoprost
`Latanoprost
`Bimatoprost
`Travoprost
`
`(n :136)
`(n :136)
`(n :138)
`(n : 136)
`(n :136)
`(n : 138)
`
`25.7 : 3.1
`23.8 : 3.4
`22.8 : 3.6
`22.3 : 3.3
`23.7 : 2.7
`
`25.5 i 2.8
`23.8 i 3.8 '
`22.8 i 3.3
`22.0 i 3.4
`23.5 i 2.9
`
`25.7 : 2.8
`23.7 ': 3.5
`23.0 : 3.6
`22.3 i 3.7
`23.7 : 2.9
`
`Baseline
`8:00 AM
`' 12 noon
`4:00 PM
`8:00 PM
`Diurnal
`Week 12
`7.9 : 3.4
`8.7 : 3.8
`8.6 : 3.7
`17.6 i 3.7
`17.0 : 3.3
`17.1 : 3.1
`8:00 AM
`6.8 : 3.6
`7.6 i 4.0
`7.2 i 3.9
`16.8 i 3.3
`16.2 : 3.0
`16.5 i 2.7
`12 noon
`6.3 : 3.8
`6.8 : 4.0
`6.2 : 3.6
`16.4 i 3.4
`16.0 : 2.8
`16.7 : 2.5
`4:00 PM
`5.7 i 3.9
`6.5 i 3.4
`5.9 :r 3.8
`16.1 i 3.2
`15.8 i 3.0
`16.3 : 2.4
`8:00 PM
`Diurnal
`16.7 : 2.4
`16.4 : 2.8
`16.8 i 3.2
`7.0 : 3.1
`7.3 : 3.2
`6.7 : 3.2
`
`
`é
`
`L]
`U)
`+l
`9-4
`0P—i
`QN
`U.)
`Net-i
`
`Ax
`:0
`E:
`E3r".
`CW
`fig
`
`4L
`
`Baseline
`
`Week 2
`
`Week 6
`
`Week 12
`
`Visits
`FIGURE 5. Unadjusted 8:00 AM mean intraocular pressure (IOP) levels by treatment and visit (intent—to—treat population).
`
`change in IOP between baseline and week 12 as the
`dependent variable, yielded no evidence for race effect
`(P = .439, 8:00 AM; P = .227, 8:00 PM) or treatment by
`race effect (P = .681, 8:00 AM; P = .543, 8:00 PM).
`
`0 SAFETY RESULTS: At least one adverse event was
`reported by 87/136 (64.0%) patients receiving latanoprost,
`
`104/137 (75.9%) of those in the bimatoprost group, and
`95/138 (68.8%) of those treated with travoprost (Table 3).
`Fewer latanoprost’treated patients reported an ocular ad;
`verse event compared with those receiving bimatoprost or
`travoprost
`(P = .003 for difference among the three
`treatments; P < .001 for difference between latanoprost
`and bimatoprost). Compared with latanoprost’treated or
`
`VOL. 135, No. 5
`
`COMPARING LATANOPROST, BIMATOPROST, AND TRAVOPROST
`
`695
`
`

`

`
`
` 25
`
`
`Baseline
`
`Week 12
`
`24
`
`23
`
`772
`-r
`21
`20
`.
`19
`
`E?)
`:1:
`a
`E
`'V
`E
`5-},
`if
`O
`j
`
`a 32
`
`.
`
`
`
`8:00 AM
`
`12 Noon
`
`4:00 PM
`
`8:00 PM
`
`Measurement Times
`
`FIGURE 6. Unadjusted mean intraocular pressure (IOP) levels by treatment and measurement time at baseline and week 12
`(intent—to—treat population).
`
`
`travoprost’treated patients, a larger proportion of those
`treated with bimatoprost reported an adverse event related
`to a study medication (P = .015 for difference among the
`three treatments; P < .001 for difference between latanO’
`prost and bimatoprost).
`Table 4 summarizes ocular adverse events reported by
`more than 2% Of patients in any treatment group. The
`most frequently reported events were hyperemia and eye
`irritation. In all, 94/137 (68.6%) bimatoprost patients,
`80/138 (58.0%) travoprost patients, and 64/136 (47.1%)
`Iatanoprost patients reported ocular hyperemia as an ad;
`verse event (P = .001 for difference between Iatanoprost
`and bimatoprost). The mean onset day Of reporting hyper,
`emia was about 24 days for all
`treatments. A larger
`proportion Of hyperemia adverse events was ongoing at the
`study end in the bimatoprost (67/110, 60.9%) and tra’
`voprost (53/90, 58.9%) groups than in patients treated
`with Iatanoprost (33/71, 46.5%). In all, 21/137 (15.3%)
`patients receiving bimatoprost, 14/138 (10.1%) patients
`treated with travoprost, and 8/136 (5.9%) Iatanoprost;
`treated patients reported moderate hyperemia. In addition,
`4/137 (2.9%) patients in the bimatoprost group, 3/138
`(2.2%) receiving travoprost, and 1/136 (0.7%) receiving
`Iatanoprost reported severe hyperemia. One patient in the
`travoprost group discontinued from the study owing to a
`
`persistent “red eye” problem; one bimatoprost’treated pa;
`tient discontinued because Of multiple ocular adverse
`events, and another discontinued the drug at the end Of
`treatment because Of ocular hyperemia.
`Masked investigators’ assessments Of hyperemia were
`similar across treatments at baseline (P = .827) (Figure 9).
`Average hyperemia scores were significantly different
`among groups at both week 2 (P = .005) and week 12 (P
`= .005), however. At weeks 2 and 12, average hyperemia
`scores were lower for Iatanoprost’treated than for bimatO’
`prost’treated patients (P = .001 for both visits). Hyper;
`emia consistently was rated lowest in Iatanoprost’treated
`patients and highest in bimatoprost’treated patients, with
`those in the travoprost group receiving intermediate aver;
`age ratings. Throughout the 12 weeks Of treatment,
`the
`degree Of hyperemia associated with each medication
`remained consistent.
`
`At baseline, 5% to 7% of the patients in each treatment
`group reported eye redness when specifically asked about
`this symptom by the investigator
`(Iatanoprost, 9/136;
`bimatoprost, 10/137;
`travoprost, 7/138; P = .739). An
`increasing number Of patients reported redness over time
`in all treatment groups. At week 12, the largest proportion
`Of patients reporting redness was found in the bimatoprost
`group (46/132, 34.8%) followed by the travoprost and
`
`696
`
`AMERICAN JOURNAL OF OPHTHALMOLOGY
`
`MAY 2003
`
`

`

`l 0
`
`'Ju
`
`
`
`Mean10?Change(mmHg) —1()
`
`~15
`
`£0
`
`-25
`
`$0
`
`
`
`annopmst
`
`Bimatoprost
`
`Travoprosi
`
`Laianoprosr
`
`Bimatoprost
`
`Travoprost
`
`8:00 AM
`
`Diurnal
`
`FIGURE 7. Distributions of reductions from baseline to week 12 in 8:00 AM and diurnal mean intraocular pressure (IOP) levels
`by treatment (intent—to—treat population). The bottom and top edges of the box are the 25th and 75th percentiles, and the center
`horizontal line is the median. The central vertical lines cover about 99% of the data range, and outliers are indicated by an asterisk.
`
`latanoprost groups (36/132, 27.3%; and 21/131, 16.0%,
`respectively). Compared with bimatoprost’treated pa;
`tients, fewer of those receiving latanoprost reported red;
`ness at any postbaseline Visit (P S .01). In addition, fewer
`patients treated with latanoprost reported redness at weeks
`2 and 12 than did those treated with travoprost (P = .010
`and P = .027, respectively).
`Overall, 23/136 (16.9%) latanoprost patients, 25/137
`(18.2%) bimatoprost patients, and 23/138 (16.7%) tra’
`voprost patients reported systemic adverse events. Events
`reported by >2% of patients in any treatment group were
`nasopharyngitis, upper
`respiratory tract
`infection, and
`headache. Systemic events considered to be related to
`study medication were infrequent in any treatment group.
`Five patients (latanoprost, n = 3; bimatoprost, n = 1;
`travoprost, n = 1) reported a serious systemic adverse
`event, none of which was considered related to study
`medication. One patient with renal insufficiency died of
`acute renal failure.
`
`
`DISCUSSION
`
`WE BELIEVE THAT THIS IS THE FIRST RANDOMIZED, CON~
`
`trolled trial simultaneously comparing the IOP’lowering
`
`efficacy and safety of latanoprost, bimatoprost, and tra’
`voprost. Over 12 weeks, we found no significant differences
`in efficacy among the three medications in patients with
`open’angle glaucoma or ocular hypertension using an ITT
`analysis; results were supported by findings of per’protocol
`analyses. At the conclusion of the study, IOP measure»
`ments were significantly reduced from baseline for all three
`study groups at 8:00 AM, the primary efficacy variable, and
`neither the magnitude nor the distribution of the IOP
`reduction was statistically different among the three treat;
`ments. The 8:00 AM determination was chosen prospec’
`tively as the endpoint as it approximates the time of
`maximal IOP reduction by the three drugs13v21vzzv25’28 and
`the time of enhanced probability of pressure peaks based
`on circadian IOP patterns in studies of patients with
`glaucoma.”30 Blunting pressure peaks is a goal of glau’
`coma therapy as large diurnal fluctuations in IOP are an
`independent risk factor for the progression of disease.31 In
`addition, no significant difference in the persistence of
`pressure lowering was detected across treatments as mea’
`sured by change in mean IOP levels at week 12 at any
`individual time point or for the diurnal mean.
`We also compared simultaneously the ocular tolerability
`and systemic adverse events of latanoprost, bimatoprost,
`and travoprost based on masked’investigator grading and
`
`VOL. 135, No.5
`
`COMPARING LATANOPROST, BIMATOPROST, AND TRAVOPROST
`
`697
`
`

`

`10
`
`‘J1
`
`l!)
`
`0
`
`Latanoprost
`
`Bimatoprost
`
`Travopmst
`
`o):3
`
`
`
`MeanIOPChange
`
`A
`
`
`
`MeanIOPChange
`
`(mmH
`{mmHg)
`
`No
`
`No
`
`No
`
`Hyp‘cremm Hypcremia Hyperemm l-h'peremiu
`
`Hyperemla
`
`l-{ypercnua
`
`B
`
`Latanoprost
`
`Billiatoprost
`
`'I‘ravoprost
`
`FIGURE 8. (A) Distributions of reductions from baseline to week 12 in 8:00 AM mean intraocular pressure (IOP) levels by
`treatment and prostaglandin analogue therapy at screening (intent—to—treat population). (B) Distributions of reductions from
`baseline to week 12 in 8:00 AM mean intraocular pressure (IOP) levels by treatment and occurrence of hyperemia (investigators’
`reports) (intent—to—treat population). The bottom and top edges of the box are the 25th and 75th percentiles, and the center
`horizontal line is the median. The central vertical lines cover about 99% of the data range, and outliers are indicated by an asterisk.
`
`698
`
`AMERICAN JOURNAL OF OPHTHALMOLOGY
`
`MAY 2003
`
`

`

`
`
`TABLE 3. Frequencies of Adverse Events (Safety Population)
`
`Latanoprost (n : 136) Travoprost (n : 138) Bimatoprost (n : 137)
`
`
`No. of
`No. of
`No. of
`n
`%
`Events
`n
`%
`Events
`n
`%
`Events
`P Value
`
`
`Patients with at least one adverse event
`Patients with ocular adverse events
`
`Patients with systemic adverse events
`Patients with adverse events related to
`
`87
`73
`
`23
`70
`
`64.0
`53.7
`
`16.9
`51.5
`
`137
`110
`
`27
`90
`
`104
`101
`
`25
`94
`
`75.9
`73.7
`
`18.2
`68.6
`
`200
`162
`
`38
`140
`
`95
`89
`
`23
`81
`
`68.8
`64.5
`
`16.7
`58.7
`
`159
`129
`
`30
`108
`
`.098
`.003
`
`.933
`.015
`
`study medications
`
`
`
`TABLE 4. Ocular Adverse Events Reported by More Than 2% of Patients in Any Treatment Group: All Rando