Combination IOP Reduction Therapy in Open-Angle Glaucoma
Globally, glaucoma is a leading cause of permanent blindness. As of 2020, about 80 million people worldwide, and 3 million Americans, are affected by glaucoma. The most common form of glaucoma is open-angle glaucoma. Unfortunately, the primary risk factor for open-angle glaucoma is elevated intraocular pressure (IOP), which often exists asymptomatically in early stages. Currently, the primary therapies for glaucoma and ocular hypertension target reducing IOP. Combination IOP reduction therapy in open-angle glaucoma stands to offer improvement to current treatment options.
CURRENT GLAUCOMA TREATMENTS
Once glaucoma is detected, treatment guidelines recommend initial monotherapy with prostaglandin analogs. These drugs are effective at achieving IOP reductions in the short term, but 40-75% of glaucoma patients require multiple medications at the 2 to 5 year timeframe in therapy. In fact, insufficient IOP reduction causes 50% of glaucoma patients to switch from the first prescribed monotherapy within the first 2 years of treatment. For most patients, adding additional medications, or increasing the frequency of doses, results in extra burden and lower adherence. As a result, IOP reduction is not sufficiently maintained. Combination eye drops have been developed to combat these drug administration challenges. Many eye drop combinations for IOP reduction contain a beta blocker, which is contraindicated in many glaucoma patients. One eye drop option in these patients is a combination containing brinzolamide 10mg/mL and brimonidine 2mg/mL (called BBFC). Approved dosing three times daily has been shown to effectively reduce IOP in open-angle glaucoma patients who were refractory to prostaglandin monotherapy.
IOP REDUCTION STUDY
The purpose of this study was to measure the effectiveness of BBFC dosing twice daily for IOP reduction in open-angle glaucoma or ocular hypertension patients who failed prostaglandin monotherapy. This study is registered with ClinicalTrials.gov (NCT02419508).
This study was a six week, phase 4, randomized, double-masked, parallel group trial. It was conducted across 30 locations in 10 countries from August 7, 2015 until February 7, 2018. After selection, eligible patients were started on a prostaglandin, if he or she were not taking one, for at least 28 days prior to the start of the study. After selection, eligible patients on multiple IOP therapies were washed out prior to the study. After all patients were normalized, they were assigned 1:1 to twice daily BBFC or vehicle in addition to a prostaglandin antagonist. To avoid bias, patients, investigators, sponsors, clinic staff, and monitors were unaware of the treatment assignments through the study. Eye drop therapies were provided in identical opaque bottles identified with protocol numbers. The prostaglandin bottles were not masked.
This study was held to the standards of the Declaration of Helsinki and also was compliant with the International Conference on Harmonization, Good Clinical Practice, Consolidated Guidelines, and had its protocol approved by an Independent Ethics Committee/Institutional Review Board. Patients were given written informed consent prior to acceptance into the study.
Inclusion criteria were patients at least 18 years of age who were diagnosed with open-angle glaucoma or ocular hypertension and had mean IOP between 19 and 32 mmHg in at least one eye during both eligibility visits, which occurred after the washout period. Typically, IOP greater than 21 mmHg is considered elevated, but this study included pressures greater than 19 mmHg due to challenges during the recruitment.
PRIMARY STUDY ENDPOINTS: IOP REDUCTION
The primary endpoint of this study was a mean change in IOP from baseline to week 6, measured as an average of 0900 and 1100 time points.
The secondary endpoints of this study were mean IOP at week 6 (as an average of 0900 and 1100 time points), mean percent IOP change at week 6 (as an average of 0900 and 1100 time points), and mean and percent mean IOP change at week 6 (measured at 1100).
Safety endpoints included the occurrence and characteristics of any adverse drug events, change in best-correct visual acuity, perimety and dilated fundus examination findings, slit lamp examination, and vital sign including blood pressure and pulse rate. These safety endpoints include clinically relevant testing and examination procedures for glaucoma patients as provided by the Glaucoma Research Foundation.
IOP measurements were taken using the Goldmann applanation tonometry, and IOP was taken at 0900 and 1100 time points during eligibility and follow up appointments.
Eighty one patients per treatment group were statistically required to be included in this study in order to detect a 2 mmHg change in IOP at week 6 with 90% power. Common standard deviation of IOP change was assumed to be between 3.5 mmHg and 3.9 mmHg. In order to account for dropouts during the study, over 90 patients per treatment group were assigned.
All data was analyzed, including baseline assessments and patients who completed at least one scheduled study visit. IOP changes from baseline were analyzed using a pair-wise test at each scheduled follow up appointment. This model included factors for prostaglandin type, geographical region, treatment, visit, and treatment per visit interaction. Baseline IOP was included as a covariate. Fixed sequence testing strategies were utilized to ensure type I error was controlled and 5% significance level was used.
IOP REDUCTION STUDY RESULTS
The full analysis of data included 187 patients. 174 patients completed the study, with adverse events to IOP medication being the primary reason for dropout. The mean age of study participants analyzed was 67.2 years, 52.4% were female, and 92% were white. 81.3% of the study had a diagnoses is open-angle glaucoma, and the rest had ocular hypertension. Patient demographics between treatment groups were similar except for the BBFC group had more female participants than the vehicle group. The mean IOP at baseline was comparable between the groups.
The least squares mean change in IOP from baseline was greater in the BBFC treatment group. The treatment difference was statistically significant in favor of the BBFC group (-3.44 mmHg, 95% CI, P<0.001). The study met its primary objective.
The least squares mean IOP was 17.3 mmHg with the BBFC treatment group, and 20.75 mmHg in the vehicle group, a difference that is statistically significant. The mean percentage difference change in IOP at week 6 was higher in the BBFC group (-15.1%, P<0.001) and statistically significant. Similarly, the mean change and mean percent change from baseline were greater in the BBFC treatment group (P<0.001).
IOP equal to or less than 18 mmHg was achieved in 60% of the BBFC treatment group patients, and 20.7% of the vehicle group.
Twice daily dosing of BBFC in this study had a minimal effect on ocular perfusion pressure.
37.9% of patients in the BBFC group, and 14.1% in the vehicle group experienced at least adverse event. Ocular hyperemia was the most prevalent adverse event reported (5.3% of patients) in the BBFC group. Blurry vision was the most common adverse event reported (2.2% of patients) in the vehicle group. Dry mouth was reported in 5.3% of the BBFC treatment group patients. Once incidence of moderately severe cardiac failure was reported in the BBFC group during this study, but this instance was determined to not be related to treatment. No patients died during this study. Treatment related adverse events occurred in 22 of the BBFC treatment group patients, and in 4 patients in the vehicle group. Dropouts from the study due to adverse events occurred in 8 patients in the BBFC group and 3 patients in the vehicle group. Dropout reasons were due to the following: ocular discomfort (2 patients), arrhythmia, cardiac failure, allergic conjunctivitis, ocular hyperemia, dizziness, and anxiety.
DISCUSSION: IOP REDUCTION
Twice daily administration of BBFC given with prostaglandin was effective in this study for IOP reduction in open-angle glaucoma or ocular hypertension patients. Clinically relevant IOP reductions were present as soon as week 2, and were maintained until week 6 when the study concluded. The study met its primary objective and showed that greater IOP reduction was achieved in the BBFC treatment group compared to the vehicle group (5.6 mmHg vs 2.1 mmHg, P<0.001). This data demonstrate that twice daily dosing of BBFC with prostaglandin is effective in the treatment of patients with open-angle glaucoma or ocular hypertension who were unable to be maintained on prostaglandin alone. This has previously also been demonstrated with three times a day dosing. This finding is clinically relevant when considering that adherence to therapy is essential for IOP reduction success. Patient adherence is likely to improve when dosing frequency is less often. Furthermore, the Early Manifest Glaucoma Trial demonstrated previously that the risk of disease progression decreases 10% for each 1 mmHg reduction in IOP. The BBFC treatment group in this study showed a mean IOP reduction of 5.6 mmHg, which is a highly clinically relevant finding.
The result of this study that showed 60% of BBFC treatment patients achieved an IOP of equal to or less than 18 mmHg is relevant due to a previous meta-analysis of 822 patients (by Stewart, Kolker, Sharpe, et al.) with open-angle glaucoma that showed IOP in this range stabilized patients for an extended 5 year period.
An additional advantage of the BBFC medication is that is the only available combination product that does not contain a beta blocker. Many comorbidities such as asthma or chronic pulmonary obstructive disease prevent glaucoma patients from using other available combination therapies.
This study suggests that twice daily dosing of BBFC with prostaglandin therapy is a reasonable treatment option for patients with open-angle glaucoma or ocular hypertension when prostaglandin monotherapy is insufficient. The safety profile of this combination is congruent with those of the individual components contained within.
This study was supported financially by Novartis Pharma AG, Basel, Switzerland.
Medical writing support and editorial support was provided by Swati Bhandari, Novartis Healthcare Pvt Ltd, Hyderabad, India.
The authors of the study publication NCT02419508 declared the following potential conflicts of interest: receipt of grants/research support from Aerie, Alcon, Glaukos, Heidelberg Engineering, Iridex, Pfizer, Novartis, Sensimed, and Thea; consultation fees from Alcon, Bayer, Allergan, Pfizer, and Thea; company sponsored speaker’s bureau by Novartis, Thea, Alcon, Allergan, and Santen