FormalPara Key Summary Points

Why carry out this study?

Dorzolamide/timolol fixed combination (DTFC) as well as brimonidine/timolol fixed combination (BTFC) are commonly used in patients with glaucoma as an adjunct to prostaglandin analogue monotherapy.

No multicenter clinical trials had been designed to compare the efficacy and tolerability of fixed combinations of 0.1% brimonidine/0.5% timolol (BTFC; Aibeta®) versus 1% dorzolamide/0.5% timolol (DTFC; Cosopt®) as adjunctive therapies to prostaglandin analogues.

What was learned from the study?

Additional BTFC instillation for 8 weeks reduced intraocular pressure (IOP) by 3.55 mmHg, proving non-inferiority to the IOP reduction of DTFC instillation (by 3.60 mmHg; P < 0.0001).

Patients felt greater ocular discomfort with DTFC instillation than with BTFC instillation (P < 0.0001). More patients preferred BTFC (P < 0.0001) for comfortability because of less eye irritation.

Introduction

Pharmacotherapy is the most common initial intervention to lower intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) [1]. Prostaglandin analogues are the most frequently prescribed eye drops for patients with OAG due to their effectiveness, high tolerability, and requirement of only one daily instillation [2,3,4]. If the initial monotherapy fails to sufficiently reduce IOP, additional medications are used in combination until the desired IOP level is attained [5]. Currently, more than 50% of patients with glaucoma in developed countries take multiple IOP-lowering medications [6]. The use of multiple topical treatments reduces adherence and increases exposure to preservatives [7]. Therefore, fixed combination therapy is preferred over the separate instillation of multiple drugs.

Dorzolamide/timolol fixed combination (DTFC) therapy has been widely prescribed worldwide to patients with OAG [8], due to its IOP-lowering efficacy, which is comparable to that of prostaglandin analogues [9]. DTFC is generally administered twice daily as an adjunct to prostaglandin analogue monotherapy when further IOP reduction is desired [10, 11]. Although the IOP-lowering efficacy of anti-glaucoma drugs is critical for preventing further visual field loss, selecting a suitable drug also depends on other factors that may influence patient adherence, such as comfort upon drop instillation and overall tolerability [12]. Despite its efficacy, DTFC instillation causes ocular discomfort more frequently than other fixed combination drugs [13, 14]. Ocular comfort upon instillation is critical to the tolerability of anti-glaucoma drugs, as low tolerability is a barrier to treatment adherence [15].

Brimonidine/timolol fixed combination (BTFC) therapy, commercially available as Combigan® (Allergan, Dublin, Ireland), contains 0.5% timolol and is administered twice daily. BTFC has also been used as an adjunct to prostaglandin analogue monotherapy [16, 17]. When used as an adjunct to prostaglandin analogues, brimonidine has been reported to remarkably reduce the IOP peak compared with dorzolamide [18]. Moreover, meta-analyses of brimonidine or dorzolamide monotherapy have indicated that brimonidine reduces IOP comparably to or to a greater extent than dorzolamide [19]. Additionally, several clinical trials that compared BTFC and DTFC monotherapy demonstrated that BTFC offers considerably greater [20, 21] or comparable [22,23,24,25] reduction in IOP to DTFC. However, other studies have reported greater IOP reduction with DTFC [26]. Meanwhile, some of these comparative studies reported that patients experienced ocular discomfort, such as burning and stinging, more frequently with DTFC than with BTFC [21,22,23]. Taken together, these results suggest that BTFC might be a better candidate for patients who need either adjunctive therapy with prostaglandin analogue monotherapy or for those switching from DTFC in combination therapy with prostaglandin analogues.

Aibeta® (Senju Pharmaceutical, Osaka, Japan) is a BTFC that has been available in Japan since 2019. It contains 0.1% brimonidine, which is half the concentration of brimonidine in Combigan®. Similarly, Cosopt® (Santen, Osaka, Japan), a commercially available DTFC in Japan, contains 1% dorzolamide, while the Cosopt® available in the United States and Europe contains 2% dorzolamide. These fixed combinations were approved in Japan because 0.1% brimonidine and 1% dorzolamide resulted in reductions in IOP comparable to those with 0.2% brimonidine and 2% dorzolamide in Japanese patients with glaucoma. However, no clinical trials have compared BTFC (0.1% brimonidine) with DTFC (1% dorzolamide). The largest clinical trial to study adjunctive therapies to prostaglandin analogues compared 37 patients administered BTFC (0.2% brimonidine) with 42 patients administered DTFC (2% dorzolamide) for 3 months. It demonstrated no significant differences in IOP reduction but reported better visual comfort in the BTFC group [21].

Here, we report the Aibeta Crossover Study, a crossover, randomized, multicenter clinical trial comparing the efficacy and tolerability of BTFC and DTFC in 110 Japanese patients for 4 months to evaluate whether BTFC can be used as an alternative to DTFC, as an adjunct to prostaglandin analogues in patients with OAG or ocular hypertension.

Methods

Study Design

The Aibeta Crossover Study (jRCTs051190125) was a 4-month randomized and observer-masked crossover study conducted among 20 centers in Japan between 27 March 2020 and 24 June 2021. The Certified Review Board at the University of Fukui (CRB5180014) approved the study on 20 January 2020. The study protocol was prepared in accordance with the Declaration of Helsinki. Before enrolment, the protocol was explained to all the participants, as well as the possible risks and benefits of the interventions. All patients provided written informed consent.

Inclusion Criteria

Patients diagnosed with primary OAG, exfoliation glaucoma, or ocular hypertension who fulfilled the following criteria were included: (1) adults aged 20 years or older; (2) received monotherapy with a prostaglandin analogue ophthalmic solution for more than 90 days in the study eye; (3) IOP between 15 and 24 mmHg in the study eye during Visit 1; (4) IOP fluctuation within 3 mmHg for 90 days if diagnosed with exfoliation glaucoma; (5) IOP of 24 mmHg or lower in both eyes; (6) best-corrected visual acuity of 0.3 or better (decimal) for both eyes; and (7) requirement for additional reduction in IOP determined by the examiner.

Exclusion Criteria

The exclusion criteria were as follows: (1) anti-glaucoma medication other than prostaglandin analogue monotherapy within 28 days before Visit 1; (2) corticosteroid administration within 28 days before Visit 1; (3) history of prior glaucoma surgery in the study eye; (4) prior intraocular surgery in the study eye within 90 days before Visit 1 in the study eye; (5) intraocular injection, sub-Tenon, or subconjunctival injection of a triamcinolone acetonide in the study eye within 180 days before Visit 1; (6) other active ocular diseases in the study eye; (7) severe visual field defects (either mean deviation of -20 db or lower in Humphrey visual field test or mean defect of 20 db or higher in Octopus visual field test) in the study eye; and (8) contraindications or a history of allergy to BTFC, DTFC, or the components included in these ophthalmic solutions.

Data Collection

If both eyes fulfilled the inclusion and exclusion criteria, the studies were conducted in the eye with higher IOP at Visit 1, and, if the IOP was equal in both eyes, the studies were performed on the right eye. Figure 1 depicts the study design. At the baseline visit (Visit 1), patients receiving prostaglandin analogue monotherapy for 90 days or more were randomized in a 1:1 ratio to one of the two crossover sequences of 8-week instillation with either BTFC containing 0.1% brimonidine and 0.5% timolol (Aibeta) or DTFC containing 1% dorzolamide and 0.5% timolol (Cosopt) (Period 1). They were subsequently crossed over to the alternative treatment for 8 additional weeks (Period 2). A permuted block randomization on electronic data capture was stratified by the following balancing factors: diagnosis (OAG, ocular hypertension, or exfoliation glaucoma), age (< 60 years, ≥ 60 years), and IOP (low: ≥ 15.0 mmHg, < 18.0 mmHg; moderate: ≥ 18.0 mmHg, ≤ 21.0 mmHg; high: ≥ 21.0 mmHg, ≤ 24.0 mmHg) during Visit 1. Patients continued treatment with prostaglandin analogues throughout the study and were instructed to instil additional BTFC or DTFC twice daily (9–11 am and 9–11 pm). The investigators were blinded during treatment, while patients were unmasked to facilitate differentiation between the two eye drops. IOP was measured with Goldmann applanation tonometry, and the IOP values at each time point were represented as the mean of two consecutive measurements. If the difference between the two measurements was ≥ 3 mmHg, a third measurement was taken, and the median was used. IOP at Visit 1 was measured twice at the 2-h interval between 9 and 11 am without instillation. At Visits 2–5, IOP was measured just before the instillation of the fixed combinations (0 h) and 2 h after instillation on each visit. Missing IOP data were imputed at Week 8 by the last observation carried forward method. The study visits were planned on Visit 1 (prostaglandin analogue monotherapy) and scheduled as Visit 2 (Week 4 in Period 1), Visit 3 (Week 8 in Period 1), Visit 4 (Week 4 in Period 2), and Visit 5 (Week 8 in Period 2). The examiners evaluated safety based on the occurrence of adverse events and assessment of ocular parameters with slit-lamp biomicroscopy variables (at each visit), ophthalmoscopy variables (at Visits 1, 3, and 5), and best-corrected visual acuity (at Visits 1, 3, and 5).

Fig. 1
figure 1

Study design. BTFC 0.1% brimonidine/0.5% timolol fixed combination; DTFC 1% dorzolamide/0.5% timolol fixed combination

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Questionnaire

Patients were instructed to fill out the record form for each instillation to measure adherence, and those with adherence < 75% at any visit were excluded from analysis. The patients filled out the comfortability questionnaire on the record form after the initial instillation of each first- and second-stage trial drug. Specifically, patients were asked to rate the severity of eye irritation, eye pain, and blurred vision in the study eye [27,28,29,30]. The evaluation parameters in the comfortability questionnaire were set with reference to the frequency of side effects related to ocular discomfort due to BTFC and DTFC. The scores were scaled on an 11-point scale between 0 (none) and 10 (most serious). Upon completion of the trial, patients recorded their preferred trial drug (options: BTFC, DTFC, either drug) and the reason for their choices (options: because of no or minimal eye irritation/because of no or minimal eye pain/because of no or minimal blurred vision/other reason) in terms of comfortability throughout the trial period.

Primary Outcome

The primary outcome of this study was the comparison of the reduction in IOP after 8 weeks of BTFC versus that after 8 weeks of DTFC. The non-inferior margin was set within 1.0 mmHg. The change in IOP was calculated as the mean of the IOP values at 0 and 2 h after the instillation of the fixed combination after the 8-week instillation minus the mean of the IOP values at 0 and 2 h at Visit 1.

Secondary Outcomes

The 0- and 2-h values and their mean were used to measure the IOP, change in IOP, and rate of change in IOP. The IOP at various time points after drug administration was compared with that at Visit 1. The IOP, change in IOP, and rate of change in IOP were compared between the two drugs. The differences in tolerability (discomfort score and preference), occurrence of adverse events, and anterior ocular findings score before and after drug administration (conjunctiva, eyelid, and cornea) were investigated for both drugs. The anterior ocular findings of the conjunctiva (hyperaemia, oedema, and follicles), eyelids (erythema and oedema), and corneal epithelium (superficial punctate keratopathy) were scored on a scale of 0 to 3 based on previous reports [31,32,33]. Score worsening by two or more points was calculated at Weeks 4 and 8 after the instillation of each fixed combination. Side effects due to the two fixed combinations were monitored throughout the study. The baseline IOP was assessed during Visit 1 (0- and 2-h values) and was classified by the median value, and a subpopulation analysis for effectiveness was conducted.

Sample Size Calculation

The number of patients required to verify that the IOP-lowering effect of BTFC was not inferior to that of DTFC by more than 1.0 mmHg at a significance level (α) of 2.5% on one side, and the power (1–ß) of 90% was calculated as 103. Therefore, the target sample size was set at 120, including a discontinuation and dropout rate of 15%.

Statistical Analysis

Statistical analyses were performed using SAS for Windows Release 9.4 Foundation (SAS Institute, Cary, NC, USA). The reduction in IOP by the two drugs was measured using the mixed-effects model. Statistical analyses of the differences in IOP between Visit 1 and other visits with each drug were performed using paired t tests. A paired t test was used to compare the IOP, change in IOP, and rate of change in IOP between the two drugs, and subpopulation analysis was performed for the same factors in the same manner. A comparison of the discomfort scores of the drugs was performed using the Wilcoxon signed-rank test. The preference was statistically analyzed using the test for a population proportion. Data for the mixed-effects model were presented as the mean ± standard error, while the other data were presented as the mean ± standard deviation. For all statistical tests, P values < 0.05 were considered statistically significant.

Results

Patient Characteristics

Figure 2 depicts the procedure used for selecting participants for this study. A total of 117 patients were assessed for eligibility. Seven patients were excluded as they did not fulfil the inclusion/exclusion criteria. Thus, 110 patients (55 in the BTFC to DTFC group and 55 in the DTFC to BTFC group) were randomized for the study, and 102 patients (52 in the BTFC to DTFC group and 50 in the DTFC to BTFC group) completed the study. No significant difference was observed in patient characteristics between the two groups (Table 1).

Fig. 2
figure 2

Patient flowchart. BTFC 0.1% brimonidine/0.5% timolol fixed combination; DTFC 1% dorzolamide/0.5% timolol fixed combination; AE adverse event

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Table 1 Patient characteristics
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Primary Outcome

The mean IOPs at each visit for the BTFC to DTFC group and the DTFC to BTFC group are shown in Fig. 3. The IOPs at all the visits after administration were significantly lower than the IOPs at Visit 1 (P < 0.0001, paired t test).

Fig. 3
figure 3

Changes in mean intraocular pressure (IOP) at 0- and 2 h for the 0.1% brimonidine/0.5% timolol fixed combination (BTFC) to 1% dorzolamide/0.5% timolol fixed combination (DTFC) group and the DTFC to BTFC group. After drug administration, the IOPs at all visits were significantly lower than those at the first visit (P < 0.0001, paired t test). Error bar standard deviation

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The mean IOP reduction at 8 weeks after BTFC administration was 3.55 ± 0.22 mmHg, while that after DTFC administration was 3.60 ± 0.22 mmHg (Fig. 4). The estimated difference in IOP between the two drugs (95% confidential interval) was 0.05 mmHg (-0.32–0.43 mmHg), which was less than the non-inferior margin (P < 0.0001, mixed-effects model). Prior to the main analysis, the carry-over effect and period effect were examined with a 10% significance level. With respect to the change in IOP 8 weeks after treatment initiation, the carry-over effect and period effect in both groups were not significant (P = 0.7991 and 0.9702, respectively).

Fig. 4
figure 4

Comparison of mean reduction in intraocular pressure (IOP) (0- and 2-h) from baseline to 8 weeks between 0.1% brimonidine/0.5% timolol fixed combination (BTFC) and 1% dorzolamide/0.5% timolol fixed combination (DTFC) groups. The estimated difference between the two drugs (95% confidential interval) was 0.05 mmHg (− 0.32 to –0.43 mmHg), which was less than the non-inferior margin (P < 0.0001, mixed-effects model). Error bar standard error

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Secondary Outcomes

Table 2 and Fig. 5 depict the IOP at each measurement time point. The IOPs at all measurement time points after drug administration were significantly lower than those at Visit 1 (P < 0.0001, paired t test). The maximal IOP reduction during the study was observed at the 2 h point, 8 weeks after the initiation of treatment. The mean IOP reduction was 4.3 ± 2.3 mmHg after BTFC administration and 3.9 ± 2.5 mmHg after DTFC administration. Compared with DTFC, BTFC had a significant lowering effect on the 2 h mean IOP at Weeks 4 and 8 after initiation. Subpopulation analysis (median classification) revealed a significant reduction in IOP in patients with a baseline IOP of ≤ 18 mmHg and > 18 mmHg, respectively.

Table 2 Changes in IOP
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Fig. 5
figure 5

Changes in intraocular pressure (IOP) (mean of 0- and 2-h) before and after the administration of 0.1% brimonidine/0.5% timolol fixed-combination (BTFC) and 1% dorzolamide/0.5% timolol fixed-combination (DTFC). The IOPs at all measurement time points after the administration were significantly lower than the IOPs during Visit 1 (P < 0.0001, paired t test). Error bar standard deviation

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Questionnaire

All discomfort scores (eye irritation, eye pain, and blurred vision) were significantly lower with BTFC than DTFC. According to crossover sequences, all discomfort scores were significantly lower for BTFC than for DTFC (P < 0.0001, Wilcoxon signed-rank test; Fig. 6). Additionally, according to the comfortability questionnaire, 84% of the patients preferred BTFC, while 4% preferred DTFC, showing a statistically significant difference (P < 0.0001, a test for a population proportion; Fig. 7). The most frequent reason behind favoring BTFC was no or minimal eye irritation.

Fig. 6
figure 6

a Evaluation scale. b–d The comparison of discomfort scores between 0.1% brimonidine/0.5% timolol fixed combination (BTFC) and 1% dorzolamide/0.5% timolol fixed combination (DTFC) groups. All discomfort scores were significantly lower with BTFC than DTFC (P < 0.0001, Wilcoxon signed-rank test). Error bar standard deviation

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Fig. 7
figure 7

a Drug preference questionnaires. A total of 84% of patients preferred the comfortability of 0.1% brimonidine/0.5% timolol fixed combination (BTFC), while 4% preferred the comfortability of 1% dorzolamide/0.5% timolol fixed combination (DTFC) (P < 0.0001, test for a population proportion). b Reasons for choosing BTFC (multiple answers allowed). The most common reason for preferring the comfortability of BTFC was no or minimal eye irritation

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Adverse Events

Regarding ocular surface conditions, score worsening by two or more points was found in the corneal epithelium during the instillations of BTFC and DTFC and in the conjunctiva during DTFC instillation (Table 3). However, the maximal frequency was as low as 2.3% and 3.5% during instillations of BTFC and DTFC, respectively.

Table 3 Score-worsening of ocular surface condition by two or more points
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Adverse events were observed in 4 of 105 patients (3.8%) treated with BTFC and 5 of 107 patients (4.7%) treated with DTFC. Moreover, side effects were observed in two patients (1.9%) treated with BTFC and three patients (2.8%) treated with DTFC. Bradycardia and Descemet folds were noted in one patient each during BTFC administration. In contrast, pain, discomfort, and irritation in the eye were noted in one patient each during DTFC administration and were recorded as side effects due to drug administration. No severe or fatal side effects were reported, and all side effects disappeared with the discontinuation of treatment.

Discussion

The aim of this study was to assess whether BTFC can be used as an alternative for DTFC as an adjunct to prostaglandin analogues in patients with OAG or ocular hypertension. This randomized, crossover, multicenter clinical trial comparing the efficacy and tolerability of BTFC and DTFC was conducted on 110 Japanese patients treated with prostaglandin analogue monotherapy. Additional BTFC instillation for 8 weeks reduced IOP by 3.55 mmHg, proving non-inferiority to the IOP reduction resulting from DTFC instillation (P < 0.0001, mixed-effects model). Both therapies showed further IOP reduction for 8 weeks in patients with OAG or ocular hypertension previously treated with prostaglandin analogue monotherapy (P < 0.0001, paired t test). Although the side effects of these drugs were rare, patients felt greater discomfort with DTFC instillation than with BTFC instillation (P < 0.0001). Thus, more patients preferred BTFC (P < 0.0001) for comfortability, which caused no or minimal eye irritation.

DTFC and BTFC have been commonly administered as adjuncts to prostaglandin analogue monotherapy when further IOP reduction is required [11, 12, 16, 17]. The superiority of either drug in terms of IOP reduction is controversial [20,21,22,23,24,25,26]. The additional IOP reduction offered by these fixed combinations has been compared in few studies, despite their common usage as adjunctive therapy with prostaglandin analogues [21]. The present study is unique because the efficacy and tolerability of these fixed combinations were compared in a randomized, crossover, multicenter clinical trial in patients previously treated with prostaglandin analogue monotherapy.

In the present study, IOP reduction by BTFC was comparable to that by DTFC, as previously reported [21,22,23,24,25]. However, a meta-analysis revealed that brimonidine monotherapy reduced IOP to a greater extent than or comparably with dorzolamide monotherapy [19]. Another meta-analysis demonstrated that brimonidine reduced IOP to a greater extent than dorzolamide when used as adjunctive therapy to prostaglandin analogues [18]. This discrepancy may be due to the 0.5% timolol included in BTFC and DTFC. Timolol provides greater IOP reduction than brimonidine or dorzolamide [34]. Thus, the difference in IOP reduction between brimonidine and dorzolamide may have been masked by the greater IOP-lowering effect of timolol included in these fixed combinations. Another possibility is that the mean IOP at the baseline was 18.3 mmHg, which was lower than that of the previous clinical trials that demonstrated a greater reduction in IOP with BTFC than with DTFC [20, 21]. The IOP at Visit 1 was < 21 mmHg in most patients on prostaglandin analogue monotherapy. The IOP reduction provided by anti-glaucoma medications is lower in eyes with normal IOP that are continuously treated with anti-glaucoma medication than in untreated eyes with high IOP [35]. In this study, IOP levels lowered by prostaglandin analogue monotherapy may have masked the difference in IOP reduction between BTFC and DTFC.

Our study reported better outcomes with BTFC than with DTFC in terms of conformability, which is consistent with previous studies comparing the two drugs [21,22,23]. The ocular discomfort may be associated with the pH difference between these two drugs. Ocular discomfort after instillation is commonly related to acidic ophthalmic solutions [36, 37]. While DTFC is formulated at a pH between 5.5 and 5.8, the pH of BTFC ranges from 6.9 to 7.3, similar to that of tear fluid. The neutral pH of the BTFC formulation likely accounts for the better comfort scores in this study. This finding may be clinically significant since ocular discomfort upon instillation of eye drops may limit medication adherence [38]. Health record data-based analyses indicated a marked inverse association between medication adherence and the rate of progression of visual field loss in patients with glaucoma [39]. Increased BTFC preference may contribute to the long-term prevention of visual field loss.

This study had a few limitations. First, the ocular discomfort beyond the study period was not evaluated. Allergic follicular conjunctivitis is a common adverse effect of brimonidine instillation that causes itching, prompting patients to discontinue the use of brimonidine solution [40]. The mean and median duration of 0.15% and 0.2% brimonidine use before the onset of allergic conjunctivitis are 266.6 and 196 days, respectively [41]. Therefore, patients could have developed discomfort later after BTFC instillation, which could have been identified if the study period had been longer. However, prospective randomized trials have reported that the combination of brimonidine and timolol reduced the incidence of brimonidine allergy [42, 43]. As the BTFC used in this study included 0.1% brimonidine and 0.5% timolol, fewer patients may have developed long-term ocular discomfort. Nevertheless, further clinical trials comparing the tolerability between the two fixed combinations are warranted. Second, we did not compare BTFC with brinzolamide/timolol fixed combination, the other carbonic anhydrase inhibitor/ß-blocker fixed combination. The fixed combination is formulated at a pH between 6.7 and 7.7, indicating neutral pH. The differences in tolerability in our study were limited to the comparison between BTFC and DTFC. Third, the patients filled out the comfortability questionnaire on the record form after the initial instillation of each first- and second-stage trial drug. Patients might have been accustomed to pain, discomfort, and irritation in their eyes during the continuous instillation of ophthalmic solutions. The scores in the comfortability questionnaire after the completion of the follow-up visits at the timing of the initial instillation might have differed from the scores in the present study. Fourth, because all recruited patients were Japanese, the data may not completely apply to other races.

Conclusions

BTFC results in IOP reduction comparable to that of DTFC in patients with OAG or ocular hypertension when used as adjunctive therapy to prostaglandin analogues. Moreover, the tolerability of BTFC is higher than that of DTFC, indicating that BTFC is a good option for patients with ocular discomfort with DTFC-prostaglandin analogue combination therapy.