- Email: [email protected]
Timolol 0.5% for Glaucoma or Ocular Hypertension: A Randomized Trial
Accepted Manuscript Adherence to Fixed-Combination Versus Unfixed Travoprost 0.004%/Timolol 0.5% for Glaucoma or Ocular Hypertension: a Randomized Trial Howard S. Barnebey, Alan L. Robin PII:
S0002-9394(16)30598-0
DOI:
10.1016/j.ajo.2016.12.002
Reference:
AJOPHT 9971
To appear in:
American Journal of Ophthalmology
Received Date: 18 August 2016 Revised Date:
6 December 2016
Accepted Date: 7 December 2016
Please cite this article as: Barnebey HS, Robin AL, Adherence to Fixed-Combination Versus Unfixed Travoprost 0.004%/Timolol 0.5% for Glaucoma or Ocular Hypertension: a Randomized Trial, American Journal of Ophthalmology (2017), doi: 10.1016/j.ajo.2016.12.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Purpose: To assess adherence to treatment with fixed-combination travoprost 0.004%/timolol 0.5% (TTFC) compared with separate containers of travoprost 0.004% and timolol 0.5% (TRAV+TIM; unfixed) using electronic dosing aids Design: Randomized, controlled, observer-masked clinical trial
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Methods: Setting: Two US clinical sites Patient Population: Eligible patients were adults diagnosed with open-angle glaucoma or ocular hypertension. Patients (n=81) were sequentially randomized 1:1 to receive TTFC or TRAV+TIM for 12 months. Intervention: TTFC was administered once daily in the morning or evening with a single dosing aid. Patients randomized to TRAV+TIM administered TRAV once daily in the evening and TIM once daily in the morning using separate dosing aids. Main Outcome Measure: Adherence with administered medication, as recorded by the dosing aids
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Results: Mean ± SD patient age was 60±10 years; most patients were male and white. Compared with TRAV+TIM (n=40), patients receiving TTFC (n=41) were consistently adherent on a greater percentage of days through month 12 (60% vs 43%). At months 1, 3, 6, and 12, 80% adherence was achieved by 71% vs 38%, 53% vs 30%, 45% vs 16%, and 32% vs 11% of patients receiving TTFC vs TRAV+TIM, respectively. Significantly more patients were adherent on ≥80% of days with TTFC compared with TRAV+TIM (P<0.001 to P=0.041). Both treatments reduced IOP from baseline, and no safety issues were identified in either group. Ocular hyperemia was the most common treatment-related adverse event (n=3/group).
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Conclusions: Patients receiving TTFC maintained better treatment adherence compared with patients receiving TRAV+TIM through 12 months of on-therapy evaluation. This suggests that, for patients requiring multiple IOP-lowering medications, a fixed combination may provide improved long-term adherence compared with unfixed therapy.
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Adherence to Fixed-Combination Versus Unfixed Travoprost 0.004%/Timolol 0.5% for Glaucoma or Ocular Hypertension: a Randomized Trial
Howard S. Barnebey1 and Alan L. Robin2
Specialty Eyecare Centre, 1920 116th Avenue NE, Bellvue, WA 98004; 2Department of Ophthalmology, Johns Hopkins University, 600 N. Wolfe Street, Baltimore, MD 21287; Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, MD 21205; University of Maryland, 419 W. Redwood Street, Baltimore, MD 21201; University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105
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Short Title: Adherence with Travoprost/Timolol
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Corresponding author: Howard S. Barnebey, MD 1920 116th Ave NE, Bellevue, WA 98004 Telephone: 425-454-3937 Fax: 425-453-6646 [email protected]
Keywords: compliance; dosing aid; DuoTrav; electronic monitoring; persistence
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Introduction
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Pharmacologic control of intraocular pressure (IOP) with topical ocular hypotensive medications is the standard of care for the initial treatment of open-angle glaucoma and ocular hypertension.1 Elevated IOP can lead to optic nerve head damage, visual field loss, or disability and blindness. Higher IOP levels are associated with increased risk for disease progression and glaucoma-related visual disability and blindness.2, 3 Ocular hypotensive therapy is effective in slowing or preventing progression of glaucoma and ocular hypertension,4-7 and maintaining long-term IOP reduction reduces the risk of vision loss. For some patients, a single medication produces sufficient IOP reduction, although many patients require treatment with more than 1 medication to achieve and maintain sufficiently low IOP.5, 6 Patient adherence with IOP-lowering treatment is crucial for the successful medical management of glaucoma; however, adherence with glaucoma medications is typically low and decreases with time.8-10 Adherence is influenced by many patient- and treatment-related variables, and treatment complexity (ie, number of individual medications and daily doses) is one of the only modifiable factors associated with suboptimal treatment adherence. For example, compared with combination medications, treatment regimens using multiple individual medications are associated with lower treatment adherence.11-16 Most fixed-combination therapies provide 2 ocular hypotensive agents in a single formulation, thereby simplifying treatment regimens and reducing the number of daily instillations. An inherent disadvantage of fixed combinations is that missed doses result in omission of both medications rather than of a single agent. Because better adherence with glaucoma therapy is associated with reduced progression of visual field defects,17, 18 understanding and improving adherence among patients with glaucoma or ocular hypertension is an important aspect of treatment. Approaches to assess adherence include patient surveys and self-reports, pharmacy refill records, and electronic dosing aids; all of which have advantages and disadvantages. For example, patients frequently overestimate their treatment adherence,19 pharmacy records cannot determine whether medications are used, and dosing aids record accidental dispensing and incorrectly instilled doses in addition to intentional, correctly administered doses. A benefit of dosing aids is that they provide a relatively objective record of the number and timing of drops dispensed using the device, although they do not record whether or not the drop actually reached the eye.20 Our objective was to assess adherence through 12 months of treatment with a fixed combination of the prostaglandin analog travoprost 0.004% and the β-blocker timolol 0.5% in a single bottle compared with 2 separate bottles containing travoprost 0.004% and timolol 0.5% in eyes with open-angle glaucoma or ocular hypertension using electronic dosing aids.
Methods Study Design This was a randomized, controlled, observer-masked clinical trial conducted at 2 sites in the United States (Seattle, WA, and Baltimore, MD) between March 2007 and January 2010 (www.ClinicalTrials.gov identifier NCT00465803). The study consisted of 2
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a screening visit followed by a washout period, a post-washout eligibility visit, and ontherapy follow-up visits conducted at days 30, 90, 180, and 365 (months 1, 3, 6, and 12, respectively). The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and the Health Insurance Portability and Accountability Act. Participating patients gave written informed consent for study participation before enrollment. All study protocols and consent forms were prospectively approved by Sterling Institutional Review Board (Sterling Independent Services, Inc., Atlanta, GA), and the study and data accumulation were carried out with approval from the Institutional Review Board.
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Patients and Study Eye Selection Eligible patients were at least 18 years old and diagnosed with open-angle glaucoma (including open-angle glaucoma with pigment dispersion and pseudoexfoliation) or ocular hypertension. Additional inclusion criteria were discontinuation of all IOP-lowering medications for the appropriate minimum washout period, determined by ocular hypotensive class, and mean post-washout IOP ≥21 mmHg in at least 1 eye and mean IOP ≤36 mmHg in both eyes. The study eye was the qualifying eye (IOP ≥21 mmHg) at the eligibility visit. Key exclusion criteria were any form of glaucoma other than open-angle glaucoma (with or without pigment dispersion or pseudoexfoliation) or ocular hypertension; any condition that precluded safe administration of a prostaglandin analog or β-blocker; history of chronic or recurrent severe inflammatory eye disease, clinically significant or progressive retinal disease, or severe ocular pathology; history of ocular trauma or intraocular surgery ≤6 months before screening; ocular laser surgery or ocular infection/inflammation ≤3 months before screening; best-corrected visual acuity (BCVA) worse than 0.60 logMAR in either eye; estimation of narrow angle (<10°) with the possibility of closure; cup-to-disc ratio >0.80 in either eye; severe central visual field loss; and pregnancy, potential of becoming pregnant during the study, or breastfeeding. Patients using non–IOP-lowering medications that may have affected IOP (eg, systemic β-blockers) were required to have a stable dosing regimen for ≥30 days before screening and throughout the study.
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Treatments All eligible patients were sequentially randomized to either the fixed combination of travoprost 0.004%/timolol 0.5% (TTFC; DuoTrav®, Alcon Laboratories, Inc., Fort Worth, TX) or unfixed travoprost 0.004% (Alcon Laboratories, Inc.) and timolol (as timolol maleate 0.5%; Falcon Pharmaceuticals Ltd., Fort Worth, TX) (TRAV+TIM) using a set of randomization numbers developed to ensure a 1:1 assignment ratio. Study medications were to be instilled in both eyes unless a potential safety issue precluded administration in the non-study eye. Patients receiving TTFC were instructed to instill 1 drop of TTFC in each eye once daily at either 8 AM or 8 PM, in accordance with patient preference, consistently for 12 months. Patients receiving TRAV+TIM were instructed to instill 1 drop of TIM once daily at 8 AM and 1 drop of TRAV once daily at 8 PM. All study medications were supplied in identical opaque bottles filled to 4.0 mL that were placed inside Travalert® Dosing Aids (Alcon Laboratories, Inc.) with the 3
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reminder functions turned off. Patients receiving TRAV+TIM used a separate dosing aid for each medication. The dosing aids recorded the time, date, and number of drops used in each instillation; dosing aids were not capable of recording misuse, such as removing medications from the aids or dispensing but not instilling drops.
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Outcomes and Assessments The primary outcome was adherence with medication administration over 12 months as recorded by the dosing aids. Patients were defined as adherent with their assigned study treatment on any given day if the associated dosing aid recorded at least 1 drop dispensed at any time during the specified 24-hour period for that day; each of the 2 dosing aids used in the TRAV+TIM group must have recorded at least 1 drop dispensed. The mean percentage of days on which patients adhered to their dosing schedules was the primary measure of adherence and was evaluated cumulatively over fixed time intervals and for the overall duration of the study. Cumulative adherence was calculated for intervals of increasing duration (ie, through 1 month, 3 months, 6 months, and 12 months). Responder analyses were performed to assess threshold levels of adherence. Patients who discontinued the study early contributed data only to the point of discontinuation. Safety variables included IOP measurements, visual field test results, gonioscopy evaluation findings, BCVA assessments, ocular signs (cornea, iris/anterior chamber, lens, eyelids, and conjunctiva), dilated fundus examinations (vitreous, retina/macula/choroid, optic nerve, cup-to-disc ratio), blood pressure, heart rate, and adverse events (AEs). IOP was measured in both eyes at all study visits by an independent operator and reader using a calibrated Goldmann applanation tonometer, after completion of BCVA and slit-lamp biomicroscopy assessments. Central threshold visual fields were assessed at screening and month 12 with habitual correction by achromatic automated perimetry with a Humphrey Field Analyzer using a 24-2 threshold field test. Gonioscopy was performed at screening and month 12 before instillation of dilating or miotic drops, and gonioscopy was graded using the modified Shaffer Grading Scale. BCVA was assessed at every study visit, before IOP measurement, using an Early Treatment Disorder Retinopathy Study (ETDRS) chart at a viewing distance of 10 feet. Ocular signs were assessed for both eyes at every visit using slit-lamp biomicroscopy. Dilated fundus examinations were conducted for both eyes at screening and month 12 visits after completion of IOP measurements. Systolic and diastolic blood pressures were recorded at every visit after 5 minutes of resting; heart rate measurements were based on a 60-second count. AE information was collected during all on-therapy visits; AEs were coded using the Medical Dictionary for Regulatory Activities, version 13.0. Statistical Analysis Adherence was analyzed in the intent-to-treat (ITT) population, defined as all patients who instilled ≥1 dose of study medication using the dosing aid and who provided ≥1 day of adherence information from the dosing aid. Safety variables were assessed in the safety population, which was defined as all patients who instilled ≥1 dose of study medication using the dosing aid.
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Patient demographics and baseline characteristics, adherence outcomes, and safety variables were summarized descriptively. Cumulative adherence was calculated for various thresholds (50%, 60%, 70%, 80%, 90%, and 95%). All threshold levels were included in adherence calculations for each cumulative time interval. Post hoc statistical analyses of potential between-group differences in the percentage of patients achieving various adherence thresholds were performed using Fisher exact tests and chi-square tests. Assuming an SD of approximately 50% of the mean percent adherence rate and mean percent adherence rates of 40%, 60%, and 80%, 80 patients (40 patients per treatment group) were determined to be sufficient to estimate treatment group differences within ±10%, ±15%, and ±20%, respectively, based on a 2-sided 95% CI.
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Patients Eighty-one patients were enrolled, randomized to treatment, and included in the ITT data set (TTFC, n=41; TRAV+TIM, n=40; Figure 1). Mean ± SD patient age was 60±10 years; 38% of patients (n=31/81) were ≥65 years old. Most patients were male (67%; n=54/81) and white (89%; n=72/81; Table 1). Patient demographic and baseline characteristics were similar between treatment groups. Ten patients discontinued the study (n=5 per treatment group). Reasons for discontinuation in the TTFC group were inadequate IOP control (n=2), sponsor request (n=2), and AE (n=1). Reasons for discontinuation in the TRAV+TIM group were inadequate IOP control, AE, nonadherence, sponsor request, and patient decision (n=1 each).
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Adherence Throughout 12 months of on-therapy evaluation, patients receiving TTFC were adherent with their dosing schedule on a greater percentage of days compared with patients receiving TRAV+TIM (Figure 2). In the first month of dosing, the cumulative mean ± SD percentage of days patients were adherent with dosing was 79±26% in the TTFC group and 67±28% in the TRAV+TIM group. The cumulative percentage of days through month 12 that patients were adherent with dosing was 60±28% and 43±27% with TTFC and TRAV+TIM, respectively. Cumulative treatment adherence at thresholds of 50% to 95% was consistently higher with TTFC compared with TRAV+TIM (Figure 3). Significantly greater percentages of patients receiving TTFC demonstrated cumulative adherence with dosing schedules on ≥80% of days through treatment months 1, 3, 6, and 12 compared with patients receiving TRAV+TIM (P<0.001 to P=0.041). However, in both treatment groups, cumulative adherence declined throughout the duration of the study. At 1 month of treatment, 37% of patients in the TTFC group (n=15/41) and 10% of patients in the TRAV+TIM group (n=4/40) achieved adherence at a threshold level of 95% of days (P=0.005). Patients receiving TTFC maintained adherence on ≥95% of days through month 3 (25%; n=10/40), month 6 (21%; n=8/38), and month 12 (16%; n=6/37), whereas no patients receiving TRAV+TIM maintained cumulative daily adherence above the 95% threshold at these time points. The threshold of adherence with dosing 5
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on ≥80% of days was maintained through 12 months by 32% of patients receiving TTFC (n=12/37) compared with 11% of patients receiving TRAV+TIM (n=4/36; P=0.028).
Discussion
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Safety The mean ± SD duration of exposure to study medications was 341±84 days in the TTFC group and 345±66 days in the TRAV+TIM group. Mean ± SD baseline IOP at the post-washout eligibility visit was similar between treatment groups (TTFC, 26.8±4.4 mmHg; TRAV+TIM, 25.5±4.1 mmHg). IOP change from baseline was also similar between groups, ranging from –7.7 mmHg and –8.7 mmHg at month 1 to –7.4 mmHg and –7.3 mmHg at month 12 with TTFC and TRAV+TIM, respectively (Figure 4). There were no trends or significant differences between treatment groups with regard to changes from baseline in systolic or diastolic blood pressure or heart rate at any visit. A similar number of patients in each treatment group experienced AEs, most of which were ocular in nature and mild or moderate in intensity (Table 2). The most common treatment-related AE in both groups was ocular hyperemia (n=3 per group). Eye pain and eye irritation were each reported for 2 patients receiving TTFC. Serious AEs unrelated to treatment were reported for 3 patients: syncope (TTFC group, n=1; severe), hip arthroplasty (TRAV+TIM group, n=1; severe), and anemia (TRAV+TIM group, n=1; moderate). No patients discontinued the study because of a serious AE. One patient in the TTFC group discontinued the study because of 3 moderate treatment-related AEs (eye irritation, ocular hyperemia, and photophobia), and 1 patient in the TRAV+TIM group discontinued because of 1 AE unrelated to treatment (alopecia; mild). We identified no safety issues or trends in either treatment group based on changes from baseline in visual field tests, gonioscopy evaluations, BCVA assessments, ocular signs, or fundus parameters. The overall safety profiles of TTFC and TRAV+TIM were similar.
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Patient adherence with IOP-lowering therapy for glaucoma or ocular hypertension is a difficult challenge for healthcare providers.9 Many individuals requiring medical therapy for glaucoma are already on multiple systemic prescription medications.21 This becomes more complex if daily nutraceuticals and other over-thecounter medications are considered. Therapies requiring separate instillation of multiple individual medications increases treatment complexity, which has been associated with decreased treatment adherence. Adherence with treatment regimens is multifactorial; however, the effect of treatment complexity as a factor in adherence can be minimized with use of fixed-combination therapies that provide multiple medications in a single formulation. The purpose of this study was to assess patient adherence with daily glaucoma medication dosing schedules when receiving a fixed-combination treatment (TTFC) compared with separate dosing of its unfixed components (TRAV+TIM) over 12 months. The once-daily dosing of TTFC and TRAV+TIM was the simplest treatment regimen possible (ie, 1 daily instillation and 2 daily instillations, respectively) and, as such, enabled the most direct comparison of adherence rates between the fixed and 6
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unfixed medications without introducing additional variables. Compared with patients receiving TRAV+TIM, patients receiving TTFC were adherent with their dosing schedule on a greater percentage of days through 1, 3, 6, and 12 months of treatment, although adherence was less than ideal. Furthermore, significantly greater percentages of patients achieved adherence at cumulative thresholds of 80% to 95% with TTFC compared with TRAV+TIM throughout the study. Notably, between-group differences in adherence were observed in the first month of treatment with regard to both the percentage of days that patients were adherent with their treatment regimen and the percentage of patients achieving higher adherence thresholds. These results were consistent with demonstrations that adherence generally decreases with increasing treatment complexity.11, 12, 15, 16 Fixed-combination therapies simplify treatment administration for patients requiring multiple IOP-lowering medications, potentially increasing adherence with dosing regimens.22 In the current study, adherence declined over time in both treatment groups, consistent with a previous 6-month assessment of adherence monitored using dosing aids,8 but appeared to decrease at a more rapid rate with TRAV+TIM than with the fixed-combination medication. This suggests that although fixed-combination therapies with once-daily dosing may promote better adherence over longer periods of time compared with separate instillation of 2 medications at different times of day,12 fixed-combination dosing does not address all factors that may play a role in treatment adherence. In addition to treatment complexity, other factors that may influence adherence include age, income, race, education, health awareness, health literacy, lifestyle, and number of concomitant eye diseases.23-25 Several studies have demonstrated that race is an important determinant of treatment adherence.23, 26, 27 In the current study, most patients in both treatment groups were white, and patient race was not significantly different between groups. Patient age was also similar between groups. Nevertheless, important differences in treatment adherence were observed with TTFC compared with TRAV+TIM. The IOP-lowering efficacy of TTFC and TRAV+TIM has been demonstrated previously.28-31 IOP change from baseline was not a primary outcome of the current study; however, both treatment regimens effectively reduced IOP from baseline. Both treatments were well tolerated, and no new safety concerns were identified with either treatment regimen. An interesting observation in this study was that, despite improved adherence in the TTFC group, IOP was similar between treatment groups at follow-up months 1, 6, and 12. IOP was not a predefined endpoint in this study, but was measured as a descriptive variable. The observation that mean IOP measured at clinic visits did not correlate with adherence rates may reflect the “white-coat compliance” phenomenon,32 in which patients increase adherence to treatment in anticipation of a clinic visit.33, 34 White-coat compliance may confound long-term assessment of IOP control, because short-term increases in adherence before a clinic visit can cause IOP to appear wellcontrolled.35 Indeed, periods of poor adherence may not be reflected in IOP measured at clinic visits because the IOP-lowering effects of many ocular hypotensive agents are evident within hours after administration.19, 36 A similar effect of increased compliance in anticipation of clinic visits was observed in a study that used microelectronic monitoring to measure adherence with pill taking.33 Although adherence dropped significantly 7
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between clinic visits, spot checks revealed that drug levels at clinic visits were within the therapeutic range. This led the authors to conclude that serum drug levels observed at follow-up visits do not represent long-term steady-state serum concentrations.33 The possibility of overestimation of adherence with treatment regimens is a potential limitation of this study. Dosing aids provide an advanced approach for measuring treatment adherence but cannot determine whether medications were instilled. Patients were considered adherent on a given day if their dosing aids recorded at least 1 drop dispensed in a 24-hour period; potential delivery of multiple drops by a dosing aid in a 24-hour period was not considered in adherence analyses. Patients elected to participate in the study and were therefore possibly healthier and more motivated than the general population. Furthermore, adherence with treatment may have been increased because of participation in a clinical trial.37 However, investigators made no additional attempts to educate patients on the importance of adherence throughout the study, and no aids for promoting adherence were discussed or provided for either treatment group. Morning versus evening dosing of TTFC was determined by individual patient preference and was not included in data analyses. The timing of daily instillations may have influenced treatment adherence, which is reported to be decreased with evening versus morning dosing.38, 39 Lastly, group sizes were relatively small and patients were predominantly white and were generally younger than those in other studies, which may limit the generalizability of study results to broader patient populations.
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Conclusions Adherence is a multifactorial issue in which the complexity of treatment regimens plays an important role. In patients with glaucoma or ocular hypertension who require multi-agent therapy, TTFC may promote improved adherence with treatment compared with TRAV+TIM. Based on this and other studies, there appears to be a clear role for fixed-combination medications when adherence is a significant issue. Additional work outlining patterns of adherence and the relationship of adherence with daily activities and proximity to scheduled physical appointments will be described in future publications.
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Acknowledgments and Disclosure a. Funding/Support This study was sponsored by Alcon Research, Ltd., Fort Worth, TX. The study sponsor participated in study design and data analysis, provided feedback on manuscript drafts, and agreed with the decision to submit the manuscript for publication.
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b. Financial Disclosures Dr. Barnebey is a consultant to Alcon, Allergan, Aerie, and Biolight. Dr. Robin is a consultant to Aerie Pharmaceuticals, ForeSight Visions, Glaukos, Biolight, and Clearside, and is on the board of the Aravind Eye Foundation.
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c. Other Acknowledgments Medical writing support was provided by Heather D. Starkey, PhD, of CHC Group, LLC (Chadds Ford, PA) and was funded by Alcon.
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Figure Legends
Figure 1. Disposition of Patients With Open-Angle Glaucoma or Ocular Hypertension Receiving Fixed-Combination Travoprost 0.004%/Timolol 0.5% or Unfixed Travoprost 0.004% + Timolol 0.5%.
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Figure 2. Cumulative Treatment Adherence To Fixed-Combination Travoprost 0.005%/Timolol 0.5% Versus Unfixed Travoprost 0.004% + Timolol 0.5% By Patients With Open-Angle Glaucoma or Ocular Hypertension. Data reflect the percentage of patients considered adherent through each time point; results are presented as mean and standard deviation. Patient percentages are indicated within top of bars; group sizes are indicated within bottom of bars.
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Figure 3. Adherence To Fixed-Combination Travoprost 0.005%/Timolol 0.5% Versus Unfixed Travoprost 0.004% + Timolol 0.5% By Threshold Level For Patients With OpenAngle Glaucoma or Ocular Hypertension At 1 Month (top left), 3 Months (top right), 6 Months (bottom left), and 12 Months (bottom right). Patient percentages are indicated within bars. P values reflect the results of chi-square tests unless otherwise indicated. *P value from Fisher exact test.
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Figure 4. Intraocular Pressure Change From Baseline in Patients With Open-Angle Glaucoma or Ocular Hypertension Receiving Fixed-Combination Travoprost 0.004%/Timolol 0.5% or Unfixed Travoprost 0.004% and Timolol 0.5%. Results are presented as mean and standard deviation. Mean intraocular pressure changes are indicated within bottom of bars; group sizes are indicated within top of bars.
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Table 1. Demographics of Patients With Open-Angle Glaucoma or Ocular Hypertension Randomized to FixedCombination Travoprost 0.004%/Timolol 0.5% or Unfixed Travoprost 0.004 + Timolol 0.5% (Intent-to-Treat Population)
61.5±9.3 44–80
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27 (65.9) 14 (34.1)
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58.7±10.2 29–76
28 (68.3) 13 (31.7)
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35 (85.4) 4 (9.8) 1 (2.4) 1 (2.4)
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2-sided t test. Chi-square test. c Fisher exact test. b
Unfixed Travoprost 0.004% + Timolol 0.5% (n=40)
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Fixed-Combination Travoprost 0.004%/Timolol 0.5% (n=41)
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Demographic Characteristic, n (%) Age, years Mean ± SD Range Distribution <65 ≥65 Sex Male Female Race White Black or African American Native Hawaiian or Pacific Islander Other
P Value 0.213a 0.439b
23 (57.5) 17 (42.5) 0.753b 26 (65.0) 14 (35.0) 0.781c 37 (92.5) 3 (7.5) 0 0
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Table 2. Summary of Treatment-Emergent Adverse Events in Patients With Open-Angle Glaucoma or Ocular Hypertension Receiving Fixed-Combination Travoprost 0.004%/Timolol 0.5% or Unfixed Travoprost 0.004% + Timolol 0.5% Fixed-Combination Unfixed Travoprost 0.004%/Timolol 0.5% Travoprost 0.004% + Timolol 0.5% Adverse Events, n (%)a (n=41) (n=40) Total adverse events, n 68 58 Serious adverse events, n 2 1 b 1 Adverse events associated with 3 discontinuation, n Treatment-related adverse events Ocular hyperemia 3 (7.3) 3 (7.5) Eye irritation 2 (4.9) 0 Eye pain 2 (4.9) 0 Pruritus 1 (2.4) 1 (2.5) Photophobia 1 (2.4) 1 (2.5) Increased intraocular pressure 1 (2.4) 0 Abnormal sensation in eye 0 1 (2.5) Conjunctival hyperemia 0 1 (2.5) c Adverse events not related to treatment Meibomian gland dysfunction 5 (12.2) 2 (5.0) Nasopharyngitis 3 (7.3) 5 (12.5) Injury 3 (7.3) 2 (5.0) Foreign body sensation 3 (7.3) 0 Blurred vision 3 (7.3) 0 Gastroesophageal reflux disease 3 (7.3) 0 Vitreous detachment 2 (4.9) 4 (10.0) Increased intraocular pressure 2 (4.9) 2 (5.0) Eyelid erythema 2 (4.9) 0 Stress at work 2 (4.9) 0 Hypertension 1 (2.4) 2 (5.0) Blepharitis 1 (2.4) 2 (5.0) Conjunctival hyperemia 0 2 (5.0)
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Optic nerve disorder
0
2 (5.0)
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Incidence of adverse events is presented as number and percentage of patients experiencing a Medical Dictionary For Regulatory Activities– coded event. Patients experiencing multiple coded events were counted for each event. b 3 events were reported for a single patient. c Adverse events not related to treatment and reported for ≥2 patients within a treatment group.
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Enrollment
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Enrolled (n=81)
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Randomized (n=81)
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Allocation
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Allocated to fixed-combination travoprost 0.004%/timolol 0.5% (n=41)
Allocated to unfixed travoprost 0.004% + timolol 0.5% (n=40)
Follow-Up
• Completed the study (n=36) • Discontinued the study (n=5) Inadequate intraocular pressure control (n=2) Sponsor request (n=2) Adverse event (n=1)
• Completed the study (n=35) • Discontinued the study (n=5) Inadequate intraocular pressure control (n=1) Sponsor request (n=1) Adverse event (n=1) Noncompliance (n=1) Patient decision to withdraw (n=1)
Analysis • Intent to treat data set (n=41) • Safety data set (n=41)
• Intent-to-treat data set (n=40) • Safety data set (n=40)
Cumulative Adherence, Percentage of Patients
120 100
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Fixed-combination travoprost 0.004%/timolol 0.5% Unfixed travoprost 0.004% + timolol 0.5%
80 79 60
67
73 65
60
56 40
47
43
20 0
(41)
(40)
1 Month
(40)
(40)
3 Months
(38)
(38)
6 Months
(37)
(36)
12 Months
P=0.003
81 73
76
60
71 P=0.007
63
50
51
40
P=0.005
38
30
37
20
23
10
10
0 0.6 0.7 0.8 0.9 Threshold Level of Adherence
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80 P=0.037
63
61
50 40
P=0.006
55 47
45 40
P=0.003
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30
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70 60
0.95
Fixed-combination travoprost 0.004%/timolol 0.5%, n=38 Unfixed travoprost 0.004% + timolol 0.5%, n=38
90
32
20 10
32
16
0 0.5
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Percentage of Patients, 6 Months
0.5
5
0.6 0.7 0.8 0.9 Threshold Level of Adherence
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83
70
Fixed-combination travoprost 0.004%/timolol 0.5%, n=40 Unfixed travoprost 0.004% + timolol 0.5%, n=40
90 80 70
78
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85
73
60
63
P=0.005* 21 0
0.95
58
50
P=0.041
63
P=0.001
53
40
45
43
P<0.001
30
30
20 10
25 10
0
0
0.5
Percentage of Patients, 12 Months
80
Percentage of Patients, 3 Months
Fixed-combination travoprost 0.004%/timolol 0.5%, n=41 Unfixed travoprost 0.004% + timolol 0.5%, n=40
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Percentage of Patients, 1 Month
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0.6 0.7 0.8 0.9 Threshold Level of Adherence
0.95
Fixed-combination travoprost 0.004%/timolol 0.5%, n=37 Unfixed travoprost 0.004% + timolol 0.5%, n=36
90 80 70 60
68
50 40
50
49
P=0.028 38
30
32
28
20
P=0.025*
19
10
19 11
3
0 0.5
0.6 0.7 0.8 Threshold Level of Adherence
0.9
16 0
0.95
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Intraocular Pressure Change From Baseline, mmHg
1 Month
0 –2
(40)
(40)
6 Months
12 Months
(38)
(38)
(36)
(35)
–7.4
–7.7
–7.4
–7.3
–4 –6 –7.7 –8
–8.7
–10 –12 –14
Fixed-combination travoprost 0.004%/timolol 0.5% Unfixed travoprost 0.004% + timolol 0.5%
S0002-9394(16)30598-0
DOI:
10.1016/j.ajo.2016.12.002
Reference:
AJOPHT 9971
To appear in:
American Journal of Ophthalmology
Received Date: 18 August 2016 Revised Date:
6 December 2016
Accepted Date: 7 December 2016
Please cite this article as: Barnebey HS, Robin AL, Adherence to Fixed-Combination Versus Unfixed Travoprost 0.004%/Timolol 0.5% for Glaucoma or Ocular Hypertension: a Randomized Trial, American Journal of Ophthalmology (2017), doi: 10.1016/j.ajo.2016.12.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Abstract:
Purpose: To assess adherence to treatment with fixed-combination travoprost 0.004%/timolol 0.5% (TTFC) compared with separate containers of travoprost 0.004% and timolol 0.5% (TRAV+TIM; unfixed) using electronic dosing aids Design: Randomized, controlled, observer-masked clinical trial
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Methods: Setting: Two US clinical sites Patient Population: Eligible patients were adults diagnosed with open-angle glaucoma or ocular hypertension. Patients (n=81) were sequentially randomized 1:1 to receive TTFC or TRAV+TIM for 12 months. Intervention: TTFC was administered once daily in the morning or evening with a single dosing aid. Patients randomized to TRAV+TIM administered TRAV once daily in the evening and TIM once daily in the morning using separate dosing aids. Main Outcome Measure: Adherence with administered medication, as recorded by the dosing aids
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Results: Mean ± SD patient age was 60±10 years; most patients were male and white. Compared with TRAV+TIM (n=40), patients receiving TTFC (n=41) were consistently adherent on a greater percentage of days through month 12 (60% vs 43%). At months 1, 3, 6, and 12, 80% adherence was achieved by 71% vs 38%, 53% vs 30%, 45% vs 16%, and 32% vs 11% of patients receiving TTFC vs TRAV+TIM, respectively. Significantly more patients were adherent on ≥80% of days with TTFC compared with TRAV+TIM (P<0.001 to P=0.041). Both treatments reduced IOP from baseline, and no safety issues were identified in either group. Ocular hyperemia was the most common treatment-related adverse event (n=3/group).
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Conclusions: Patients receiving TTFC maintained better treatment adherence compared with patients receiving TRAV+TIM through 12 months of on-therapy evaluation. This suggests that, for patients requiring multiple IOP-lowering medications, a fixed combination may provide improved long-term adherence compared with unfixed therapy.
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Adherence to Fixed-Combination Versus Unfixed Travoprost 0.004%/Timolol 0.5% for Glaucoma or Ocular Hypertension: a Randomized Trial
Howard S. Barnebey1 and Alan L. Robin2
Specialty Eyecare Centre, 1920 116th Avenue NE, Bellvue, WA 98004; 2Department of Ophthalmology, Johns Hopkins University, 600 N. Wolfe Street, Baltimore, MD 21287; Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, MD 21205; University of Maryland, 419 W. Redwood Street, Baltimore, MD 21201; University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105
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Short Title: Adherence with Travoprost/Timolol
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Corresponding author: Howard S. Barnebey, MD 1920 116th Ave NE, Bellevue, WA 98004 Telephone: 425-454-3937 Fax: 425-453-6646 [email protected]
Keywords: compliance; dosing aid; DuoTrav; electronic monitoring; persistence
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Introduction
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Pharmacologic control of intraocular pressure (IOP) with topical ocular hypotensive medications is the standard of care for the initial treatment of open-angle glaucoma and ocular hypertension.1 Elevated IOP can lead to optic nerve head damage, visual field loss, or disability and blindness. Higher IOP levels are associated with increased risk for disease progression and glaucoma-related visual disability and blindness.2, 3 Ocular hypotensive therapy is effective in slowing or preventing progression of glaucoma and ocular hypertension,4-7 and maintaining long-term IOP reduction reduces the risk of vision loss. For some patients, a single medication produces sufficient IOP reduction, although many patients require treatment with more than 1 medication to achieve and maintain sufficiently low IOP.5, 6 Patient adherence with IOP-lowering treatment is crucial for the successful medical management of glaucoma; however, adherence with glaucoma medications is typically low and decreases with time.8-10 Adherence is influenced by many patient- and treatment-related variables, and treatment complexity (ie, number of individual medications and daily doses) is one of the only modifiable factors associated with suboptimal treatment adherence. For example, compared with combination medications, treatment regimens using multiple individual medications are associated with lower treatment adherence.11-16 Most fixed-combination therapies provide 2 ocular hypotensive agents in a single formulation, thereby simplifying treatment regimens and reducing the number of daily instillations. An inherent disadvantage of fixed combinations is that missed doses result in omission of both medications rather than of a single agent. Because better adherence with glaucoma therapy is associated with reduced progression of visual field defects,17, 18 understanding and improving adherence among patients with glaucoma or ocular hypertension is an important aspect of treatment. Approaches to assess adherence include patient surveys and self-reports, pharmacy refill records, and electronic dosing aids; all of which have advantages and disadvantages. For example, patients frequently overestimate their treatment adherence,19 pharmacy records cannot determine whether medications are used, and dosing aids record accidental dispensing and incorrectly instilled doses in addition to intentional, correctly administered doses. A benefit of dosing aids is that they provide a relatively objective record of the number and timing of drops dispensed using the device, although they do not record whether or not the drop actually reached the eye.20 Our objective was to assess adherence through 12 months of treatment with a fixed combination of the prostaglandin analog travoprost 0.004% and the β-blocker timolol 0.5% in a single bottle compared with 2 separate bottles containing travoprost 0.004% and timolol 0.5% in eyes with open-angle glaucoma or ocular hypertension using electronic dosing aids.
Methods Study Design This was a randomized, controlled, observer-masked clinical trial conducted at 2 sites in the United States (Seattle, WA, and Baltimore, MD) between March 2007 and January 2010 (www.ClinicalTrials.gov identifier NCT00465803). The study consisted of 2
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a screening visit followed by a washout period, a post-washout eligibility visit, and ontherapy follow-up visits conducted at days 30, 90, 180, and 365 (months 1, 3, 6, and 12, respectively). The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and the Health Insurance Portability and Accountability Act. Participating patients gave written informed consent for study participation before enrollment. All study protocols and consent forms were prospectively approved by Sterling Institutional Review Board (Sterling Independent Services, Inc., Atlanta, GA), and the study and data accumulation were carried out with approval from the Institutional Review Board.
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Patients and Study Eye Selection Eligible patients were at least 18 years old and diagnosed with open-angle glaucoma (including open-angle glaucoma with pigment dispersion and pseudoexfoliation) or ocular hypertension. Additional inclusion criteria were discontinuation of all IOP-lowering medications for the appropriate minimum washout period, determined by ocular hypotensive class, and mean post-washout IOP ≥21 mmHg in at least 1 eye and mean IOP ≤36 mmHg in both eyes. The study eye was the qualifying eye (IOP ≥21 mmHg) at the eligibility visit. Key exclusion criteria were any form of glaucoma other than open-angle glaucoma (with or without pigment dispersion or pseudoexfoliation) or ocular hypertension; any condition that precluded safe administration of a prostaglandin analog or β-blocker; history of chronic or recurrent severe inflammatory eye disease, clinically significant or progressive retinal disease, or severe ocular pathology; history of ocular trauma or intraocular surgery ≤6 months before screening; ocular laser surgery or ocular infection/inflammation ≤3 months before screening; best-corrected visual acuity (BCVA) worse than 0.60 logMAR in either eye; estimation of narrow angle (<10°) with the possibility of closure; cup-to-disc ratio >0.80 in either eye; severe central visual field loss; and pregnancy, potential of becoming pregnant during the study, or breastfeeding. Patients using non–IOP-lowering medications that may have affected IOP (eg, systemic β-blockers) were required to have a stable dosing regimen for ≥30 days before screening and throughout the study.
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Treatments All eligible patients were sequentially randomized to either the fixed combination of travoprost 0.004%/timolol 0.5% (TTFC; DuoTrav®, Alcon Laboratories, Inc., Fort Worth, TX) or unfixed travoprost 0.004% (Alcon Laboratories, Inc.) and timolol (as timolol maleate 0.5%; Falcon Pharmaceuticals Ltd., Fort Worth, TX) (TRAV+TIM) using a set of randomization numbers developed to ensure a 1:1 assignment ratio. Study medications were to be instilled in both eyes unless a potential safety issue precluded administration in the non-study eye. Patients receiving TTFC were instructed to instill 1 drop of TTFC in each eye once daily at either 8 AM or 8 PM, in accordance with patient preference, consistently for 12 months. Patients receiving TRAV+TIM were instructed to instill 1 drop of TIM once daily at 8 AM and 1 drop of TRAV once daily at 8 PM. All study medications were supplied in identical opaque bottles filled to 4.0 mL that were placed inside Travalert® Dosing Aids (Alcon Laboratories, Inc.) with the 3
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reminder functions turned off. Patients receiving TRAV+TIM used a separate dosing aid for each medication. The dosing aids recorded the time, date, and number of drops used in each instillation; dosing aids were not capable of recording misuse, such as removing medications from the aids or dispensing but not instilling drops.
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Outcomes and Assessments The primary outcome was adherence with medication administration over 12 months as recorded by the dosing aids. Patients were defined as adherent with their assigned study treatment on any given day if the associated dosing aid recorded at least 1 drop dispensed at any time during the specified 24-hour period for that day; each of the 2 dosing aids used in the TRAV+TIM group must have recorded at least 1 drop dispensed. The mean percentage of days on which patients adhered to their dosing schedules was the primary measure of adherence and was evaluated cumulatively over fixed time intervals and for the overall duration of the study. Cumulative adherence was calculated for intervals of increasing duration (ie, through 1 month, 3 months, 6 months, and 12 months). Responder analyses were performed to assess threshold levels of adherence. Patients who discontinued the study early contributed data only to the point of discontinuation. Safety variables included IOP measurements, visual field test results, gonioscopy evaluation findings, BCVA assessments, ocular signs (cornea, iris/anterior chamber, lens, eyelids, and conjunctiva), dilated fundus examinations (vitreous, retina/macula/choroid, optic nerve, cup-to-disc ratio), blood pressure, heart rate, and adverse events (AEs). IOP was measured in both eyes at all study visits by an independent operator and reader using a calibrated Goldmann applanation tonometer, after completion of BCVA and slit-lamp biomicroscopy assessments. Central threshold visual fields were assessed at screening and month 12 with habitual correction by achromatic automated perimetry with a Humphrey Field Analyzer using a 24-2 threshold field test. Gonioscopy was performed at screening and month 12 before instillation of dilating or miotic drops, and gonioscopy was graded using the modified Shaffer Grading Scale. BCVA was assessed at every study visit, before IOP measurement, using an Early Treatment Disorder Retinopathy Study (ETDRS) chart at a viewing distance of 10 feet. Ocular signs were assessed for both eyes at every visit using slit-lamp biomicroscopy. Dilated fundus examinations were conducted for both eyes at screening and month 12 visits after completion of IOP measurements. Systolic and diastolic blood pressures were recorded at every visit after 5 minutes of resting; heart rate measurements were based on a 60-second count. AE information was collected during all on-therapy visits; AEs were coded using the Medical Dictionary for Regulatory Activities, version 13.0. Statistical Analysis Adherence was analyzed in the intent-to-treat (ITT) population, defined as all patients who instilled ≥1 dose of study medication using the dosing aid and who provided ≥1 day of adherence information from the dosing aid. Safety variables were assessed in the safety population, which was defined as all patients who instilled ≥1 dose of study medication using the dosing aid.
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Patient demographics and baseline characteristics, adherence outcomes, and safety variables were summarized descriptively. Cumulative adherence was calculated for various thresholds (50%, 60%, 70%, 80%, 90%, and 95%). All threshold levels were included in adherence calculations for each cumulative time interval. Post hoc statistical analyses of potential between-group differences in the percentage of patients achieving various adherence thresholds were performed using Fisher exact tests and chi-square tests. Assuming an SD of approximately 50% of the mean percent adherence rate and mean percent adherence rates of 40%, 60%, and 80%, 80 patients (40 patients per treatment group) were determined to be sufficient to estimate treatment group differences within ±10%, ±15%, and ±20%, respectively, based on a 2-sided 95% CI.
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Patients Eighty-one patients were enrolled, randomized to treatment, and included in the ITT data set (TTFC, n=41; TRAV+TIM, n=40; Figure 1). Mean ± SD patient age was 60±10 years; 38% of patients (n=31/81) were ≥65 years old. Most patients were male (67%; n=54/81) and white (89%; n=72/81; Table 1). Patient demographic and baseline characteristics were similar between treatment groups. Ten patients discontinued the study (n=5 per treatment group). Reasons for discontinuation in the TTFC group were inadequate IOP control (n=2), sponsor request (n=2), and AE (n=1). Reasons for discontinuation in the TRAV+TIM group were inadequate IOP control, AE, nonadherence, sponsor request, and patient decision (n=1 each).
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Adherence Throughout 12 months of on-therapy evaluation, patients receiving TTFC were adherent with their dosing schedule on a greater percentage of days compared with patients receiving TRAV+TIM (Figure 2). In the first month of dosing, the cumulative mean ± SD percentage of days patients were adherent with dosing was 79±26% in the TTFC group and 67±28% in the TRAV+TIM group. The cumulative percentage of days through month 12 that patients were adherent with dosing was 60±28% and 43±27% with TTFC and TRAV+TIM, respectively. Cumulative treatment adherence at thresholds of 50% to 95% was consistently higher with TTFC compared with TRAV+TIM (Figure 3). Significantly greater percentages of patients receiving TTFC demonstrated cumulative adherence with dosing schedules on ≥80% of days through treatment months 1, 3, 6, and 12 compared with patients receiving TRAV+TIM (P<0.001 to P=0.041). However, in both treatment groups, cumulative adherence declined throughout the duration of the study. At 1 month of treatment, 37% of patients in the TTFC group (n=15/41) and 10% of patients in the TRAV+TIM group (n=4/40) achieved adherence at a threshold level of 95% of days (P=0.005). Patients receiving TTFC maintained adherence on ≥95% of days through month 3 (25%; n=10/40), month 6 (21%; n=8/38), and month 12 (16%; n=6/37), whereas no patients receiving TRAV+TIM maintained cumulative daily adherence above the 95% threshold at these time points. The threshold of adherence with dosing 5
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on ≥80% of days was maintained through 12 months by 32% of patients receiving TTFC (n=12/37) compared with 11% of patients receiving TRAV+TIM (n=4/36; P=0.028).
Discussion
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Safety The mean ± SD duration of exposure to study medications was 341±84 days in the TTFC group and 345±66 days in the TRAV+TIM group. Mean ± SD baseline IOP at the post-washout eligibility visit was similar between treatment groups (TTFC, 26.8±4.4 mmHg; TRAV+TIM, 25.5±4.1 mmHg). IOP change from baseline was also similar between groups, ranging from –7.7 mmHg and –8.7 mmHg at month 1 to –7.4 mmHg and –7.3 mmHg at month 12 with TTFC and TRAV+TIM, respectively (Figure 4). There were no trends or significant differences between treatment groups with regard to changes from baseline in systolic or diastolic blood pressure or heart rate at any visit. A similar number of patients in each treatment group experienced AEs, most of which were ocular in nature and mild or moderate in intensity (Table 2). The most common treatment-related AE in both groups was ocular hyperemia (n=3 per group). Eye pain and eye irritation were each reported for 2 patients receiving TTFC. Serious AEs unrelated to treatment were reported for 3 patients: syncope (TTFC group, n=1; severe), hip arthroplasty (TRAV+TIM group, n=1; severe), and anemia (TRAV+TIM group, n=1; moderate). No patients discontinued the study because of a serious AE. One patient in the TTFC group discontinued the study because of 3 moderate treatment-related AEs (eye irritation, ocular hyperemia, and photophobia), and 1 patient in the TRAV+TIM group discontinued because of 1 AE unrelated to treatment (alopecia; mild). We identified no safety issues or trends in either treatment group based on changes from baseline in visual field tests, gonioscopy evaluations, BCVA assessments, ocular signs, or fundus parameters. The overall safety profiles of TTFC and TRAV+TIM were similar.
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Patient adherence with IOP-lowering therapy for glaucoma or ocular hypertension is a difficult challenge for healthcare providers.9 Many individuals requiring medical therapy for glaucoma are already on multiple systemic prescription medications.21 This becomes more complex if daily nutraceuticals and other over-thecounter medications are considered. Therapies requiring separate instillation of multiple individual medications increases treatment complexity, which has been associated with decreased treatment adherence. Adherence with treatment regimens is multifactorial; however, the effect of treatment complexity as a factor in adherence can be minimized with use of fixed-combination therapies that provide multiple medications in a single formulation. The purpose of this study was to assess patient adherence with daily glaucoma medication dosing schedules when receiving a fixed-combination treatment (TTFC) compared with separate dosing of its unfixed components (TRAV+TIM) over 12 months. The once-daily dosing of TTFC and TRAV+TIM was the simplest treatment regimen possible (ie, 1 daily instillation and 2 daily instillations, respectively) and, as such, enabled the most direct comparison of adherence rates between the fixed and 6
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unfixed medications without introducing additional variables. Compared with patients receiving TRAV+TIM, patients receiving TTFC were adherent with their dosing schedule on a greater percentage of days through 1, 3, 6, and 12 months of treatment, although adherence was less than ideal. Furthermore, significantly greater percentages of patients achieved adherence at cumulative thresholds of 80% to 95% with TTFC compared with TRAV+TIM throughout the study. Notably, between-group differences in adherence were observed in the first month of treatment with regard to both the percentage of days that patients were adherent with their treatment regimen and the percentage of patients achieving higher adherence thresholds. These results were consistent with demonstrations that adherence generally decreases with increasing treatment complexity.11, 12, 15, 16 Fixed-combination therapies simplify treatment administration for patients requiring multiple IOP-lowering medications, potentially increasing adherence with dosing regimens.22 In the current study, adherence declined over time in both treatment groups, consistent with a previous 6-month assessment of adherence monitored using dosing aids,8 but appeared to decrease at a more rapid rate with TRAV+TIM than with the fixed-combination medication. This suggests that although fixed-combination therapies with once-daily dosing may promote better adherence over longer periods of time compared with separate instillation of 2 medications at different times of day,12 fixed-combination dosing does not address all factors that may play a role in treatment adherence. In addition to treatment complexity, other factors that may influence adherence include age, income, race, education, health awareness, health literacy, lifestyle, and number of concomitant eye diseases.23-25 Several studies have demonstrated that race is an important determinant of treatment adherence.23, 26, 27 In the current study, most patients in both treatment groups were white, and patient race was not significantly different between groups. Patient age was also similar between groups. Nevertheless, important differences in treatment adherence were observed with TTFC compared with TRAV+TIM. The IOP-lowering efficacy of TTFC and TRAV+TIM has been demonstrated previously.28-31 IOP change from baseline was not a primary outcome of the current study; however, both treatment regimens effectively reduced IOP from baseline. Both treatments were well tolerated, and no new safety concerns were identified with either treatment regimen. An interesting observation in this study was that, despite improved adherence in the TTFC group, IOP was similar between treatment groups at follow-up months 1, 6, and 12. IOP was not a predefined endpoint in this study, but was measured as a descriptive variable. The observation that mean IOP measured at clinic visits did not correlate with adherence rates may reflect the “white-coat compliance” phenomenon,32 in which patients increase adherence to treatment in anticipation of a clinic visit.33, 34 White-coat compliance may confound long-term assessment of IOP control, because short-term increases in adherence before a clinic visit can cause IOP to appear wellcontrolled.35 Indeed, periods of poor adherence may not be reflected in IOP measured at clinic visits because the IOP-lowering effects of many ocular hypotensive agents are evident within hours after administration.19, 36 A similar effect of increased compliance in anticipation of clinic visits was observed in a study that used microelectronic monitoring to measure adherence with pill taking.33 Although adherence dropped significantly 7
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between clinic visits, spot checks revealed that drug levels at clinic visits were within the therapeutic range. This led the authors to conclude that serum drug levels observed at follow-up visits do not represent long-term steady-state serum concentrations.33 The possibility of overestimation of adherence with treatment regimens is a potential limitation of this study. Dosing aids provide an advanced approach for measuring treatment adherence but cannot determine whether medications were instilled. Patients were considered adherent on a given day if their dosing aids recorded at least 1 drop dispensed in a 24-hour period; potential delivery of multiple drops by a dosing aid in a 24-hour period was not considered in adherence analyses. Patients elected to participate in the study and were therefore possibly healthier and more motivated than the general population. Furthermore, adherence with treatment may have been increased because of participation in a clinical trial.37 However, investigators made no additional attempts to educate patients on the importance of adherence throughout the study, and no aids for promoting adherence were discussed or provided for either treatment group. Morning versus evening dosing of TTFC was determined by individual patient preference and was not included in data analyses. The timing of daily instillations may have influenced treatment adherence, which is reported to be decreased with evening versus morning dosing.38, 39 Lastly, group sizes were relatively small and patients were predominantly white and were generally younger than those in other studies, which may limit the generalizability of study results to broader patient populations.
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Conclusions Adherence is a multifactorial issue in which the complexity of treatment regimens plays an important role. In patients with glaucoma or ocular hypertension who require multi-agent therapy, TTFC may promote improved adherence with treatment compared with TRAV+TIM. Based on this and other studies, there appears to be a clear role for fixed-combination medications when adherence is a significant issue. Additional work outlining patterns of adherence and the relationship of adherence with daily activities and proximity to scheduled physical appointments will be described in future publications.
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Acknowledgments and Disclosure a. Funding/Support This study was sponsored by Alcon Research, Ltd., Fort Worth, TX. The study sponsor participated in study design and data analysis, provided feedback on manuscript drafts, and agreed with the decision to submit the manuscript for publication.
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b. Financial Disclosures Dr. Barnebey is a consultant to Alcon, Allergan, Aerie, and Biolight. Dr. Robin is a consultant to Aerie Pharmaceuticals, ForeSight Visions, Glaukos, Biolight, and Clearside, and is on the board of the Aravind Eye Foundation.
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c. Other Acknowledgments Medical writing support was provided by Heather D. Starkey, PhD, of CHC Group, LLC (Chadds Ford, PA) and was funded by Alcon.
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References 1. American Academy of Ophthalmology Glaucoma Panel. Preferred Practice Pattern® Guidelines. Primary Open-Angle Glaucoma. San Francisco, CA: American Academy of Ophthalmology; 2010. 2. Peters D, Bengtsson B, Heijl A. Factors associated with lifetime risk of openangle glaucoma blindness. Acta Ophthalmol 2014;92(5):421-425. 3. Stewart WC, Kolker AE, Sharpe ED, et al. Long-term progression at individual mean intraocular pressure levels in primary open-angle and exfoliative glaucoma. Eur J Ophthalmol 2008;18(5):765-770. 4. Heijl A, Leske MC, Bengtsson B, Hyman L, Hussein M, Early Manifest Glaucoma Trial G. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol 2002;120(10):12681279. 5. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120(6):701-713. 6. Lichter PR, Musch DC, Gillespie BW, et al. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology 2001;108(11):1943-1953. 7. Miglior S, Zeyen T, Pfeiffer N, et al. Results of the European Glaucoma Prevention Study. Ophthalmology 2005;112(3):366-375. 8. Rossi GC, Pasinetti GM, Scudeller L, Tinelli C, Milano G, Bianchi PE. Monitoring adherence rates in glaucoma patients using the Travatan Dosing Aid. A 6-month study comparing patients on travoprost 0.004% and patients on travoprost 0.004%/timolol 0.5% fixed combination. Expert Opin Pharmacother 2010;11(4):499-504. 9. Reardon G, Kotak S, Schwartz GF. Objective assessment of compliance and persistence among patients treated for glaucoma and ocular hypertension: a systematic review. Patient Prefer Adherence 2011;5:441-463. 10. Waterman H, Evans JR, Gray TA, Henson D, Harper R. Interventions for improving adherence to ocular hypotensive therapy. Cochrane Database Syst Rev 2013;4:CD006132. 11. Djafari F, Lesk MR, Harasymowycz PJ, Desjardins D, Lachaine J. Determinants of adherence to glaucoma medical therapy in a long-term patient population. J Glaucoma 2009;18(3):238-243. 12. Robin AL, Novack GD, Covert DW, Crockett RS, Marcic TS. Adherence in glaucoma: objective measurements of once-daily and adjunctive medication use. Am J Ophthalmol 2007;144(4):533-540. 13. Tsai JC, McClure CA, Ramos SE, Schlundt DG, Pichert JW. Compliance barriers in glaucoma: a systematic classification. J Glaucoma 2003;12(5):393-398. 14. Schwartz G, Burk C, Bennett T, Patel VD. Adherence and persistence with glaucoma therapy: brimonidine/timolol versus dorzolamide/timolol and various two-bottle combinations. J Clin Exp Ophthalmol 2012;3(8):1-6. 15. Robin AL, Covert D. Does adjunctive glaucoma therapy affect adherence to the initial primary therapy? Ophthalmology 2005;112(5):863-868. 10
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Higginbotham EJ, Hansen J, Davis EJ, Walt JG, Guckian A. Glaucoma medication persistence with a fixed combination versus multiple bottles. Curr Med Res Opin 2009;25(10):2543-2547. Rossi GC, Pasinetti GM, Scudeller L, Radaelli R, Bianchi PE. Do adherence rates and glaucomatous visual field progression correlate? Eur J Ophthalmol 2011;21(4):410-414. Sleath B, Blalock S, Covert D, et al. The relationship between glaucoma medication adherence, eye drop technique, and visual field defect severity. Ophthalmology 2011;118(12):2398-2402. Okeke CO, Quigley HA, Jampel HD, et al. Adherence with topical glaucoma medication monitored electronically: the Travatan Dosing Aid study. Ophthalmology 2009;116(2):191-199. Stone JL, Robin AL, Novack GD, Covert DW, Cagle GD. An objective evaluation of eyedrop instillation in patients with glaucoma. Arch Ophthalmol 2009;127(6):732-736. Covert D, Robin AL, Novack GD. Systemic medications and glaucoma patients. Ophthalmology 2005;112(10):1849. Hollo G, Topouzis F, Fechtner RD. Fixed-combination intraocular pressurelowering therapy for glaucoma and ocular hypertension: advantages in clinical practice. Expert Opin Pharmacother 2014;15(12):1737-1747. Dreer LE, Girkin C, Mansberger SL. Determinants of medication adherence to topical glaucoma therapy. J Glaucoma 2012;21(4):234-240. Muir KW, Santiago-Turla C, Stinnett SS, et al. Health literacy and adherence to glaucoma therapy. Am J Ophthalmol 2006;142(2):223-226. Muir KW, Ventura A, Stinnett SS, Enfiedjian A, Allingham RR, Lee PP. The influence of health literacy level on an educational intervention to improve glaucoma medication adherence. Patient Educ Couns 2012;87(2):160-164. Friedman DS, Okeke CO, Jampel HD, et al. Risk factors for poor adherence to eyedrops in electronically monitored patients with glaucoma. Ophthalmology 2009;116(6):1097-1105. Sleath B, Robin AL, Covert D, Byrd JE, Tudor G, Svarstad B. Patient-reported behavior and problems in using glaucoma medications. Ophthalmology 2006;113(3):431-436. Pfeiffer N, Scherzer ML, Maier H, et al. Safety and efficacy of changing to the travoprost/timolol maleate fixed combination (DuoTrav) from prior mono- or adjunctive therapy. Clin Ophthalmol 2010;4:459-466. Konstas AG, Voudouragkaki IC, Boboridis KG, et al. 24-hour efficacy of travoprost/timolol BAK-free versus latanoprost/timolol fixed combinations in patients insufficiently controlled with latanoprost. Adv Ther 2014;31(6):592-603. Gross RL, Sullivan EK, Wells DT, Mallick S, Landry TA, Bergamini MV. Pooled results of two randomized clinical trials comparing the efficacy and safety of travoprost 0.004%/timolol 0.5% in fixed combination versus concomitant travoprost 0.004% and timolol 0.5%. Clin Ophthalmol 2007;1(3):317-322. Schuman JS, Katz GJ, Lewis RA, et al. Efficacy and safety of a fixed combination of travoprost 0.004%/timolol 0.5% ophthalmic solution once daily for open-angle glaucoma or ocular hypertension. Am J Ophthalmol 2005;140(2):242-250.
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Feinstein AR. On white-coat effects and the electronic monitoring of compliance. Arch Intern Med 1990;150(7):1377-1378. Cramer JA, Scheyer RD, Mattson RH. Compliance declines between clinic visits. Arch Intern Med 1990;150(7):1509-1510. Feldman SR, Camacho FT, Krejci-Manwaring J, Carroll CL, Balkrishnan R. Adherence to topical therapy increases around the time of office visits. J Am Acad Dermatol 2007;57(1):81-83. Schwartz GF, Quigley HA. Adherence and persistence with glaucoma therapy. Surv Ophthalmol 2008;53(suppl 1):S57-68. Orzalesi N, Rossetti L, Invernizzi T, Bottoli A, Autelitano A. Effect of timolol, latanoprost, and dorzolamide on circadian IOP in glaucoma or ocular hypertension. Invest Ophthalmol Vis Sci 2000;41(9):2566-2573. Andrade S. Compliance in the real world. Value Health 1998;1(3):171-173. Ford BA, Gooi M, Carlsson A, Crichton AC. Morning dosing of once-daily glaucoma medication is more convenient and may lead to greater adherence than evening dosing. J Glaucoma 2013;22(1):1-4. Kahook MY, Noecker RJ. Evaluation of adherence to morning versus evening glaucoma medication dosing regimens. Clin Ophthalmol 2007;1(1):79-83.
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Figure Legends
Figure 1. Disposition of Patients With Open-Angle Glaucoma or Ocular Hypertension Receiving Fixed-Combination Travoprost 0.004%/Timolol 0.5% or Unfixed Travoprost 0.004% + Timolol 0.5%.
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Figure 2. Cumulative Treatment Adherence To Fixed-Combination Travoprost 0.005%/Timolol 0.5% Versus Unfixed Travoprost 0.004% + Timolol 0.5% By Patients With Open-Angle Glaucoma or Ocular Hypertension. Data reflect the percentage of patients considered adherent through each time point; results are presented as mean and standard deviation. Patient percentages are indicated within top of bars; group sizes are indicated within bottom of bars.
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Figure 3. Adherence To Fixed-Combination Travoprost 0.005%/Timolol 0.5% Versus Unfixed Travoprost 0.004% + Timolol 0.5% By Threshold Level For Patients With OpenAngle Glaucoma or Ocular Hypertension At 1 Month (top left), 3 Months (top right), 6 Months (bottom left), and 12 Months (bottom right). Patient percentages are indicated within bars. P values reflect the results of chi-square tests unless otherwise indicated. *P value from Fisher exact test.
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Figure 4. Intraocular Pressure Change From Baseline in Patients With Open-Angle Glaucoma or Ocular Hypertension Receiving Fixed-Combination Travoprost 0.004%/Timolol 0.5% or Unfixed Travoprost 0.004% and Timolol 0.5%. Results are presented as mean and standard deviation. Mean intraocular pressure changes are indicated within bottom of bars; group sizes are indicated within top of bars.
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Table 1. Demographics of Patients With Open-Angle Glaucoma or Ocular Hypertension Randomized to FixedCombination Travoprost 0.004%/Timolol 0.5% or Unfixed Travoprost 0.004 + Timolol 0.5% (Intent-to-Treat Population)
61.5±9.3 44–80
CR
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27 (65.9) 14 (34.1)
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58.7±10.2 29–76
28 (68.3) 13 (31.7)
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35 (85.4) 4 (9.8) 1 (2.4) 1 (2.4)
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2-sided t test. Chi-square test. c Fisher exact test. b
Unfixed Travoprost 0.004% + Timolol 0.5% (n=40)
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Demographic Characteristic, n (%) Age, years Mean ± SD Range Distribution <65 ≥65 Sex Male Female Race White Black or African American Native Hawaiian or Pacific Islander Other
P Value 0.213a 0.439b
23 (57.5) 17 (42.5) 0.753b 26 (65.0) 14 (35.0) 0.781c 37 (92.5) 3 (7.5) 0 0
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Table 2. Summary of Treatment-Emergent Adverse Events in Patients With Open-Angle Glaucoma or Ocular Hypertension Receiving Fixed-Combination Travoprost 0.004%/Timolol 0.5% or Unfixed Travoprost 0.004% + Timolol 0.5% Fixed-Combination Unfixed Travoprost 0.004%/Timolol 0.5% Travoprost 0.004% + Timolol 0.5% Adverse Events, n (%)a (n=41) (n=40) Total adverse events, n 68 58 Serious adverse events, n 2 1 b 1 Adverse events associated with 3 discontinuation, n Treatment-related adverse events Ocular hyperemia 3 (7.3) 3 (7.5) Eye irritation 2 (4.9) 0 Eye pain 2 (4.9) 0 Pruritus 1 (2.4) 1 (2.5) Photophobia 1 (2.4) 1 (2.5) Increased intraocular pressure 1 (2.4) 0 Abnormal sensation in eye 0 1 (2.5) Conjunctival hyperemia 0 1 (2.5) c Adverse events not related to treatment Meibomian gland dysfunction 5 (12.2) 2 (5.0) Nasopharyngitis 3 (7.3) 5 (12.5) Injury 3 (7.3) 2 (5.0) Foreign body sensation 3 (7.3) 0 Blurred vision 3 (7.3) 0 Gastroesophageal reflux disease 3 (7.3) 0 Vitreous detachment 2 (4.9) 4 (10.0) Increased intraocular pressure 2 (4.9) 2 (5.0) Eyelid erythema 2 (4.9) 0 Stress at work 2 (4.9) 0 Hypertension 1 (2.4) 2 (5.0) Blepharitis 1 (2.4) 2 (5.0) Conjunctival hyperemia 0 2 (5.0)
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Optic nerve disorder
0
2 (5.0)
a
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Incidence of adverse events is presented as number and percentage of patients experiencing a Medical Dictionary For Regulatory Activities– coded event. Patients experiencing multiple coded events were counted for each event. b 3 events were reported for a single patient. c Adverse events not related to treatment and reported for ≥2 patients within a treatment group.
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Enrollment
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Enrolled (n=81)
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Randomized (n=81)
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Allocation
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Allocated to fixed-combination travoprost 0.004%/timolol 0.5% (n=41)
Allocated to unfixed travoprost 0.004% + timolol 0.5% (n=40)
Follow-Up
• Completed the study (n=36) • Discontinued the study (n=5) Inadequate intraocular pressure control (n=2) Sponsor request (n=2) Adverse event (n=1)
• Completed the study (n=35) • Discontinued the study (n=5) Inadequate intraocular pressure control (n=1) Sponsor request (n=1) Adverse event (n=1) Noncompliance (n=1) Patient decision to withdraw (n=1)
Analysis • Intent to treat data set (n=41) • Safety data set (n=41)
• Intent-to-treat data set (n=40) • Safety data set (n=40)
Cumulative Adherence, Percentage of Patients
120 100
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Fixed-combination travoprost 0.004%/timolol 0.5% Unfixed travoprost 0.004% + timolol 0.5%
80 79 60
67
73 65
60
56 40
47
43
20 0
(41)
(40)
1 Month
(40)
(40)
3 Months
(38)
(38)
6 Months
(37)
(36)
12 Months
P=0.003
81 73
76
60
71 P=0.007
63
50
51
40
P=0.005
38
30
37
20
23
10
10
0 0.6 0.7 0.8 0.9 Threshold Level of Adherence
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80 P=0.037
63
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50 40
P=0.006
55 47
45 40
P=0.003
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70 60
0.95
Fixed-combination travoprost 0.004%/timolol 0.5%, n=38 Unfixed travoprost 0.004% + timolol 0.5%, n=38
90
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20 10
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16
0 0.5
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Percentage of Patients, 6 Months
0.5
5
0.6 0.7 0.8 0.9 Threshold Level of Adherence
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70
Fixed-combination travoprost 0.004%/timolol 0.5%, n=40 Unfixed travoprost 0.004% + timolol 0.5%, n=40
90 80 70
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60
63
P=0.005* 21 0
0.95
58
50
P=0.041
63
P=0.001
53
40
45
43
P<0.001
30
30
20 10
25 10
0
0
0.5
Percentage of Patients, 12 Months
80
Percentage of Patients, 3 Months
Fixed-combination travoprost 0.004%/timolol 0.5%, n=41 Unfixed travoprost 0.004% + timolol 0.5%, n=40
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0.6 0.7 0.8 0.9 Threshold Level of Adherence
0.95
Fixed-combination travoprost 0.004%/timolol 0.5%, n=37 Unfixed travoprost 0.004% + timolol 0.5%, n=36
90 80 70 60
68
50 40
50
49
P=0.028 38
30
32
28
20
P=0.025*
19
10
19 11
3
0 0.5
0.6 0.7 0.8 Threshold Level of Adherence
0.9
16 0
0.95
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Intraocular Pressure Change From Baseline, mmHg
1 Month
0 –2
(40)
(40)
6 Months
12 Months
(38)
(38)
(36)
(35)
–7.4
–7.7
–7.4
–7.3
–4 –6 –7.7 –8
–8.7
–10 –12 –14
Fixed-combination travoprost 0.004%/timolol 0.5% Unfixed travoprost 0.004% + timolol 0.5%