Elevated intraocular pressure (IOP) is the major risk factor for development of primary open-angle glaucoma (POAG), and higher IOP levels are associated with increased risk of glaucoma-related blindness [
However, many patients require multiple IOP-lowering agents to achieve or maintain sufficient IOP reduction [
Brinzolamide 1%/timolol maleate 0.5% fixed-combination ophthalmic suspension (BTFC; AZARGA, Alcon Laboratories, Inc., Fort Worth, TX) has been demonstrated to effectively lower IOP in patients with POAG or OH, including those transitioned because of insufficient reduction in IOP with previous therapy [
The purpose of this study was to evaluate the efficacy and safety of adding BTFC to PGA monotherapy in patients with POAG or OH who were responsive to but inadequately controlled by their PGA monotherapy.
This was a 12-week, prospective, interventional, single-arm, open-label study conducted at 5 sites in Austria and Spain from March 2011 to April 2013 (registration identifiers: ClinicalTrials.gov,
This study was approved by the Ethikkommission der Stadt Wien (Austria) and CEIC Fundación Oftalmológica del Mediterráneo (Spain) and was performed in compliance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice. Before screening, patients provided written informed consent using an ethics board-approved consent form.
Eligible patients were aged ≥18 years with an existing clinical diagnosis of OH, POAG, or pigment dispersion glaucoma in both eyes. Additional inclusion criteria were IOP responsive to but insufficiently controlled by PGA monotherapy after ≥4 weeks of treatment before screening; baseline IOP (on PGA therapy) ≥20 mmHg in at least 1 eye (the study eye) and ≤35 mmHg in both eyes; and best-corrected visual acuity (BCVA) of 6/60 Snellen (
Key exclusion criteria were medical history of allergy, hypersensitivity, or poor tolerance to any components of the study medications; any primary or secondary glaucoma other than POAG, OH, or pigment dispersion glaucoma; narrow angle with complete or partial closure in either eye; progressive retinal or optic nerve disease other than glaucoma; corneal dystrophies or concurrent conjunctivitis, keratitis, or uveitis in either eye; history or risk of uveitis or cystoid macular edema; history of herpes simplex; any abnormality in the study eye preventing reliable applanation tonometry or fundus/anterior chamber examination; intraocular conventional or laser surgery <3 months before screening; any cardiac or pulmonary condition that precluded safe administration of a topical
The primary efficacy outcome was the mean change in IOP from baseline, when patients were receiving PGA monotherapy, to week 12, when patients were receiving BTFC plus PGA. Other assessments included the mean change in IOP from baseline to week 4, percentage of patients reaching the target IOP of ≤18 mmHg at week 12, and mean change in patient experience survey responses from baseline to week 12. IOP measurements were performed at baseline, week 4, and week 12 by Goldmann applanation tonometry; tonometers were calibrated before patient screening was initiated, and IOP measurements for individual patients were performed by the same operator using the same tonometer at all visits. The patient experience survey was administered at the baseline visit and at week 12. Symptom severity was defined as minimal (symptom present but barely noticeable), mild (symptom definitely present but does not limit activity), moderate (symptom present and severe enough to partially limit activity), or severe (symptom present and is incapacitating).
Safety was assessed by monitoring adverse event (AE) reports. Ocular signs and BCVA at weeks 4 and 12 were also assessed. Ocular signs were assessed in both eyes at each study visit by slit-lamp biomicroscopy of the eyelids, conjunctiva, cornea, iris, anterior chamber, and lens. Findings were graded as 0.5 (trace), 1 (mild), 2 (moderate), or 3 (severe). BCVA was measured using a Snellen visual acuity chart at each study visit; if >1 error occurred on a given line, values were rounded up.
Efficacy outcomes were analyzed in the intent-to-treat (ITT) population (i.e., all patients who received study medication and had at least 1 on-therapy study visit) and in the per-protocol (PP) population (i.e., all patients who received study medication, completed all study visits, and had no major protocol deviations) using data from the study eye. Safety outcomes were analyzed using data for all patients who received study medication.
Mean IOP change from baseline measured at week 12 was analyzed by 2-sided paired
A power calculation determined that completion of the study by ≥40 patients was sufficient to detect a difference in mean IOP ≥1.5 mmHg (week 12 versus baseline; SD = 2.8 mmHg) with 90% power. To ensure that ≥40 patients completed the study, the target enrollment was 50 patients.
Forty-seven patients were enrolled and included in the safety and ITT data sets; 38 patients completed the study. Most patients were aged ≥66 years (72.3%,
Efficacy data were similar in the ITT and PP data sets; results for the ITT population are presented. IOP (mean ± SD) was
IOP reduction from baseline at weeks 4 and 12. Bars represent mean IOP ± SD; mean IOP reduction from baseline is indicated inside bars. IOP = intraocular pressure. Baseline versus week 12,
Percentage of patients with IOP ≤18 mmHg and >18 mmHg at baseline and week 12. Patient percentages are indicated inside bars. IOP = intraocular pressure.
There were no significant differences between baseline and week 12 in the number of patients who reported experiencing a symptom or event on the patient experience survey (Table
Patient experience survey data.
Incidence and severity | Patients, |
|
||
---|---|---|---|---|
Baseline |
Week 12 |
|||
Do you experience or have you noticed | At this moment | Immediately following instillation of study medication | ||
|
||||
Pain in or around your eyes when exposed to light? | Yes | 5 (10.6) | 5 (12.8) | 0.753 |
Minimal | 0 | 1 (20.0) | 0.072 |
|
Mild | 0 | 1 (20.0) | ||
Moderate | 1 (20.0) | 3 (60.0) | ||
Severe | 4 (80.0) | 0 | ||
Blurred or dim vision? | Yes | 9 (19.2) | 14 (35.9) | 0.081 |
Minimal | 5 (55.6) | 6 (42.9) | 0.733 |
|
Mild | 2 (22.2) | 3 (21.4) | ||
Moderate | 2 (22.2) | 5 (35.7) | ||
Severe | 0 | 0 | ||
Stinging or burning? | Yes | 14 (29.8) | 12 (30.8) | 0.921 |
Minimal | 3 (21.4) | 7 (53.9) | 0.035 |
|
Mild | 9 (64.3) | 2 (15.4) | ||
Moderate | 2 (14.3) | 4 (30.8) | ||
Severe | 0 | 0 | ||
A feeling that something is in your eyes or under your lids? | Yes | 11 (23.4) | 11 (28.2) | 0.611 |
Minimal | 2 (18.2) | 4 (40.0) | 0.385 |
|
Mild | 4 (36.4) | 4 (40.0) | ||
Moderate | 5 (45.5) | 2 (20.0) | ||
Severe | 0 | 0 | ||
Deep pain in or around your eyes? | Yes | 3 (6.4) | 3 (7.7) | 0.812 |
Minimal | 0 | 1 (33.3) | 0.368 |
|
Mild | 1 (33.3) | 0 | ||
Moderate | 2 (66.7) | 2 (66.7) | ||
Severe | 0 | 0 | ||
Redness in your eyes |
Yes | 13 (27.7) | 11 (28.2) | 0.955 |
Minimal | 5 (38.5) | 3 (27.3) | 0.366 |
|
Mild | 4 (30.8) | 7 (63.6) | ||
Moderate | 3 (23.1) | 1 (9.1) | ||
Severe | 1 (7.7) | 0 |
A total of 28 AEs were reported by 21 patients (Table
Adverse events (safety population).
Episodes, |
|
---|---|
Patients experiencing |
21 (44.7) |
Adverse event severity | |
Mild | 23 (82.1) |
Moderate | 4 (14.3) |
Severe | 1 (3.6) |
Adverse event | |
Headache | 3 (10.7) |
Allergic conjunctivitis | 1 (3.6) |
Allergic rhinitis | 1 (3.6) |
Ankle pain | 1 (3.6) |
Burning/eyelid swelling | 1 (3.6) |
Blurred vision | 1 (3.6) |
Conjunctival discomfort | 1 (3.6) |
Corneal superficial keratitis | 1 (3.6) |
Crusting of lashes | 1 (3.6) |
Dry eye | 1 (3.6) |
Eye pain | 1 (3.6) |
Lid erythema | 1 (3.6) |
Metallic taste | 1 (3.6) |
Ocular foreign body sensation | 1 (3.6) |
Pseudostenocardia |
1 (3.6) |
Punctate keratopathy | 1 (3.6) |
Rhinitis sicca | 1 (3.6) |
Scheduled knee total endoprosthesis due to |
1 (3.6) |
Stomachache | 1 (3.6) |
Subjective poorer vision | 1 (3.6) |
Tinnitus | 1 (3.6) |
Tiredness and insomnia | 1 (3.6) |
Trace keratitis | 1 (3.6) |
Upper respiratory infection | 1 (3.6) |
Worsening of dorsal pain | 1 (3.6) |
Unknown |
1 (3.6) |
Slit-lamp observations were similar among visits. At baseline, observations for eyelids, conjunctiva, cornea, iris, anterior chamber, and fundus were normal for most patients (57.4% to 100.0%); abnormalities were reported as “trace” or “mild” for most eyes. Examination of the lens at baseline was abnormal for most patients (72.3%); however, most abnormalities were reported as “trace” or “mild.” BCVA was unchanged from baseline to week 4 or week 12.
Reducing IOP to minimize disease progression is the standard of care for glaucoma and OH. Several studies have demonstrated that maintaining sufficiently low IOP may slow or prevent progression of visual field defects. For many patients, long-term monotherapy does not maintain target IOP, and many patients benefit from a combination of 3 ocular hypotensive agents [
At baseline, when patients were receiving only PGA monotherapy, mean IOP was 23.1 mmHg. After 12 weeks of adjunctive BTFC therapy, mean IOP decreased by 6.0 mmHg to 17.2 mmHg. This reduction was observed at week 4 and was maintained through study completion. IOP was >18 mmHg in all patients at baseline, but at week 12, 70% of patients achieved the target IOP of ≤18 mmHg. The most common AE was headache, which was reported by 2 patients, and nearly all AEs were mild or moderate in severity. BCVA and slit-lamp biomicroscopy observations were unchanged from baseline throughout the study.
Maintaining IOP levels ≤18 mmHg may decrease the risk of glaucoma progression. A meta-analysis of 5 retrospective studies of patients with POAG or exfoliative glaucoma with ≥5 years of follow-up demonstrated that glaucoma progressed in 51% of patients with IOP >18 mmHg, whereas 78% of patients with mean IOP of 18 mmHg did not progress [
Our findings are in agreement with previous reports describing increased IOP-lowering efficacy of 3-medication combinations that included a PGA, a carbonic anhydrase inhibitor, and a
The AEs observed in this study were consistent with the known side effects of BTFC and topical PGAs [
Potential limitations of this study include the single-arm, open-label design and 12-week study duration. Patients’ baseline IOP may have been influenced by noncompliance with the prior medication, and adherence to study medication may have been increased because of participation in a clinical trial. Future studies with multiarm or crossover designs and longer follow-up durations would be valuable.
The use of different PGAs in this study was intentional, as it was meant to reflect clinical practice where a variety of PGAs are used based on the patient’s profile and the physician’s preference. Although not powered to show differences between groups, analysis by PGA type (travoprost and latanoprost) verified that IOP decreased significantly for both treatment groups when BTFC was added. However, if a specific PGA and brinzolamide/timolol combination were not to lower IOP, the effect would be masked because the mean change in IOP was calculated across all PGA types.
In conclusion, BTFC adjunctive therapy reduced IOP when added to a PGA in patients with OH or POAG whose IOP was poorly controlled with PGA monotherapy alone. IOP reductions were evident after 4 weeks of combined BTFC plus PGA therapy and were maintained through 12 weeks. BTFC was well tolerated, and the ocular AEs reported were consistent with the current BTFC safety profile. Adding adjunctive BTFC therapy may provide a safe and effective option for patients requiring additional IOP reduction beyond that provided by a PGA.
Anton Hommer has received research support from Alcon, Allergan, and Santen; has received honoraria or consultation fees from Alcon, Allergan, Bausch & Lomb, Heidelberg, Merck, and Santen; and has participated in speakers bureaus sponsored by Alcon, Allergan, Merck, and Santen. Douglas A. Hubatsch is an employee of Alcon. Juan Cano-Parra has received research support from Alcon. This study was sponsored by Alcon Research, Ltd., Fort Worth, TX, USA. Medical writing support was provided by Heather D. Starkey, Ph.D., of Complete Healthcare Communications, Inc. (Chadds Ford, PA), and was funded by Alcon.