A (randomized/prospective/pilot) study comparing the efficacy of Selective Laser Trabeculoplasty versus brimonidine tartrate 0.2%/timolol maleate 0.5% (Combigan, Allergan inc. Irvine, CA/USA) in lowering intraocular pressure as adjunct therapy in Primary Open Angle Glaucoma.

Purpose: To compare the intraocular pressure lowering efficacy of selective laser trabeculoplasty to brimonidine tartrate 0.2%/timolol maleate 0.5% (FCBT, Combigan, Allergan inc. Irvine, CA/USA) in patients with uncontrolled primary open-angle glaucoma on a prostaglandin analog alone. A secondary outcome was to evaluate the complication rates of selective laser trabeculoplasty. Patients and Methods: Twenty-three patients were randomized to two treatment groups within this prospective, observer-masked single site, all optometrist, pilot study. Group 1 (N=12) received 360 degrees of selective laser trabeculoplasty as additional treatment while Group 2 (N=11) was started on FCBT. Outcomes of both groups were measured at eight weeks. Results: Both treatment regimens were found to be statistically significant in lowering IOP when used as adjunct therapy. The average IOP reduction for Group 1 and Group 2 was 28.43% (SD = .17) and 28.22% (SD = .12) respectively. The incidence of an intraocular pressure spike following SLT in this patient population was found to be 8.3%. No major complications were observed in this study. Conclusion: Selective laser trabeculoplasty and brimonidine tartrate 0.2%/timolol maleate 0.5% (FCBT, Combigan, Allergan inc. Irvine, CA/USA) were shown to be equivalent in lowering intraocular pressure in uncontrolled primary open angle glaucoma patients when used as adjunct therapy for patients on a prostaglandin analog. Additionally, this is the first prospective study of optometrists performing selective laser trabeculoplasty. Although this study had a small sample size, the results appeared to show that efficacy and complication rates were comparable to previously published data; however, these results need to be confirmed with a larger multi-centered trial.

28.22% (SD = .12) respectively. The incidence of an intraocular pressure spike following SLT in this patient population was found to be 8.3%. No major complications were observed in this study. Conclusion: Selective laser trabeculoplasty and brimonidine tartrate 0.2%/timolol maleate 0.5% (FCBT, Combigan, Allergan inc. Irvine, CA/USA) were shown to be equivalent in lowering intraocular pressure in uncontrolled primary open angle glaucoma patients when used as adjunct therapy for patients on a prostaglandin analog. Additionally, this is the first prospective study of optometrists performing selective laser trabeculoplasty. Although this study had a small sample size, the results appeared to show that efficacy and complication rates were comparable to previously published data; however, these results need to be confirmed with a larger multi-centered trial. involves the patient in decision-making about treatment."(8) Inaccessibility of nonpharmacologic treatments have historically and continue to limit some patients to only medical therapy when other treatments may be better suited for their care. However, legislation in several states has modernized patient access to laser glaucoma treatments.

5
A potential shift in paradigm thinking between medical and laser therapy is evolving and will shape future choices for adjunct treatment in patients who fail prostaglandin analog monotherapy. Several studies have previously looked at using SLT as initial therapy. (6,(9)(10)(11)(12) To the authors' knowledge this is the first reported study comparing SLT to the combination drop brimonidine tartrate 0.2%/timolol maleate 0.5% (Combigan, Allergan, Inc. Irvine, CA/USA) in a head-to-head trial in uncontrolled POAG patients on a PGA.
This study was designed to compare brimonidine tartrate 0.2%/timolol maleate 0.5% and SLT in providing satisfactory outcomes as adjunct treatment to prostaglandin analogs. The safety of SLT was also evaluated and compared to reported standards.

Methods
This was a prospective, randomized, observer-masked pilot study performed by optometrists at a single site. The study was conducted in accordance with all the ethical principles outlined by the Declaration of Helsinki and was approved by the institutional review board at the University of Pikeville. The study adheres to all CONSORT guidelines.
All subjects signed an informed consent prior to participating in the study.
The primary purpose of this study was to compare the intraocular pressure lowering efficacy of Selective Laser Trabeculoplasty to the beta blocker and alpha-2 adrenergic agonist fixed combination medicine, brimonidine tartrate 0.2%/timolol maleate 0.5% (Combigan, Allergan inc. Irvine, CA/USA), in patients with primary open-angle glaucoma who were not controlled on a prostaglandin analog alone. The main endpoint was the intraocular pressure reduction of Selective Laser Trabeculoplasty and brimonidine tartrate 0.2%/timolol maleate 0.5% at eight weeks. A secondary outcome was to evaluate the complication rates and efficacy of SLT procedures when performed by optometrists.
Eligible subjects were adult patients aged 25 to 90 years old with uncontrolled POAG who were being treated with PGA monotherapy. Consecutive patients, between October 2015 6 and July 2018, meeting the inclusion criteria were asked to participate in the study.
Parallel design was used with the intended allocation ratio of 1:1. Exclusion criteria consisted of: a best corrected visual acuity worse than 20/40, history of angle closure or an occludable angle on gonioscopy, untreated IOP less than or equal to 21 mmHg, patients who have used a second IOP lowering medication in the past two months, angle recession on gonioscopy, pseudoexfoliation glaucoma, pigment dispersion glaucoma, prior incisional glaucoma surgery, prior Microinvasive Glaucoma Surgery, previous Selective Laser Trabeculoplasty or Argon Laser Trabeculoplasty, previous Laser Peripheral Iridotomy, previous refractive surgery, inflammatory eye disease, contraindication to any of the topical medicines including asthma, chronic obstructive pulmonary disease, bradycardia, or a hypersensitivity reaction, a change in dosage, or addition of, a systemic medication that could affect IOP during the study, women who were pregnant or who intended to become pregnant during the study (as verbally asked during the medical history and consenting process, no formal pregnancy test was administered for this study), or patients with significant dementia who were not able to fully comprehend the informed consent.
Subjects enrolled in the study were randomized with simple randomization, using concealed envelopes, to either receive 360 degrees of SLT treatment or use brimonidine tartrate 0.2%/timolol maleate 0.5% twice a day (q12h). If the patient needed additional treatment in both eyes, then the second eye received the same treatment as the first; however, only one eye was eligible to participate in the study. The eye with the higher baseline intraocular pressure was chosen to be the study eye. If the baseline intraocular pressure was equal in both eyes, then the right eye was chosen as the study eye. All participants continued to use their PGA once a day at nighttime during the study.
Compliance in each group was monitored using a daily drop log.
A baseline exam was performed and included a detailed ocular, family, social, and medical 7 history. Additionally, blood pressure, pulse, pupils, extraocular muscles, visual acuity, Goldmann applanation tonometry, gonioscopy, pachymetry, and a slit lamp exam were conducted. Participants randomized to the SLT treatment arm had a one-hour IOP check to monitor for IOP spikes. Any rise in IOP above 10 mm Hg from baseline at the one-hour follow-up was treated with brimonidine tartrate 0.2%. If this did not control IOP spike, then treatment to control the IOP was at the doctor's discretion. All SLT patients also received Prednisolone acetate 1% four times a day for four days, to help improve patient comfort following the procedure.
The eight-week follow-up exam for both groups was performed by a different investigator than the enrolling doctor to ensure masking and was done within two hours of the initial baseline exam to control for diurnal IOP fluctuations. The follow-up exam included visual acuity, Goldmann applanation tonometry, blood pressure, pulse, pupils, extraocular muscles, and a slit lamp exam.
Baseline IOP was calculated by averaging two IOP measurements taken 30 minutes apart during the baseline exam. If these IOP measurements were greater than +/-2 mm Hg, then a third IOP measurement was taken 30 minutes later. At each IOP measurement, two readings were taken and averaged together.
SLT was performed using a standard protocol and followed specific study guidelines.10 A Lumenis Selecta II (Lumenis Ltd., Yokneum, Israel) was used to treat 360 degrees of the angle with 100 (+/-10) evenly spaced spots. The pigment in the angle was graded, using the Scheie scale, and the initial power setting for patients with Grade I or II pigment was set at 1.0 mj. (13) The power was then titrated in 0.1 mj steps until there was a visible response of cavitation bubbles or pigment blanching. For patients with Grade III or IV angle pigment the initial power was set at 0.8 mj.
The target sample size for this pilot study was 30 patients. Twenty-six patients met 8 enrollment criteria for the study. Three patients were excluded from the data analysis due to noncompliance, scheduling issues, and observer unmasking. Therefore, data from 23 patients was analyzed for this study. No subjects were lost to follow up. Given the effect sizes seen in the results of changes in IOP levels for each group from baseline to 8-weeks, statistical power of this sample size is 0.94.
All collected data was analyzed by computing a combination of descriptive statistics and inferential statistics (specifically frequency distributions, correlation coefficients, independent t-test, dependent t-test, two-factor analysis of variance, and Chi-square) using SPSS v. 24.

Results
Patients were evenly distributed between the two study groups ( Table 1). The first group (n=12) received 360 degrees of SLT in one eye and the second group (n=11) received brimonidine tartrate 0.2%/timolol maleate 0.5% bid in one eye. The average age of patients was 66 years old in both groups, although the variability was larger in Group 1. The gender distribution was also similar between both groups, approximately 55 percent male and 45 percent female. However, the racial distribution of the two groups was not similar. While the first group was half Caucasian and half African-American, the second group was overwhelmingly Caucasian (82%).
In addition, there were differences between the two groups in the brand of PGA eye drops used by the patients, with Group 1 being relatively equally distributed between the three brands while almost three-fourths of the patients in Group 2 used Lumigan 0.01% (Allergan, Inc. Irvine, CA/USA) eye drops. The patients were also dissimilar in the amount of pigmentation in the posterior trabecular meshwork with two-thirds of the patients in Group 1 being at Grade II while patients in Group 2 ranged from Grade 0 to Grade III. 9 Table 1

. Participant Demographics
The average SLT parameters for all procedures performed in this study are found in Table 2.
IOP was significantly reduced in both groups from the baseline visit to the eight week follow up (Table 3) Table 3. Average Change in Intraocular Pressure between the Two Groups Statistically, SLT was equivalent to brimonidine tartrate 0.2%/timolol maleate 0.5% at reducing IOP at eight weeks. There was no significant difference in the average percent IOP reduction between SLT patients (M = 28.43%, SD = .17) and patients who used drops (M = 28.22%, SD = .12), t(21) = -.034. p = .973. Patients from both groups in this study experienced an average 6-7 mmHg reduction after eight weeks, these results indicate that patients receiving either of these treatments have a 0.95 confidence of experiencing a 3-4 mmHg reduction from their baseline IOP after eight weeks.
Further analysis looking at the effect size, which emphasizes the magnitude of the difference rather than confounding it with the sample size, found that the size of the difference in IOP reduction was larger for Group 1 (d=1.86, large) than for Group 2 (d=1.50, large). Additionally, a larger share of patients from Group 2 (90.9%) experienced a 15 percent or higher IOO reduction than the share from Group 1 (75.0%), Χ2 (1, N=23) = 1.03, p=.315. This difference was even more pronounced with a 20 percent or higher IOP reduction. Group 2 achieved a 20% or higher IOP reduction 81.8%, while Group 1 achieved it 58.3%, Χ2 (1, N=23) = 1.50, p=.221. However, neither the effect size, the 15% reduction, or the 20% reduction was statistically or clinically significant.
Additional differences were found when analyzing the percent change in IOP by the gonioscopy pigment grades for each group, F(1, 6) = 1.103, p = .405 (Table 4). For patients receiving 360 degrees of SLT in one eye (Group 1), the average percent reduction was greater at Grade II, while for patients receiving brimonidine tartrate 0.2%/timolol maleate 0.5% bid in one eye (Group 2), the average percent reduction was greater at grade 1. Table 4. Average Percent Change in Intraocular Pressure with Gonioscopy Pigment by Group At the 20 percent or higher IOP reduction level, there was a statistical difference between the gonioscopy pigment grades, F(3) = 3.776, p = .034; but not between SLT and drops, F(1) = 2.289, p = .151 (Table 5). However, at the 15 percent or higher IOP reduction level, there was a statistical difference between both the gonioscopy pigment grades, F(3) = 5.454, p = .010; and between SLT and drops, F(1) = 6.885, p = .019. Since these results follow what is seen in Table 4, it should not be surprising that the same conclusion can be made about angle pigment and treatment. The incidence of an IOP spike following SLT in this patient population was found to be 8.3%.
No major complications or adverse events associated with SLT such as iritis, hyphema, macular edema, or corneal edema were observed in the study. Additionally, no patients reported any adverse events or allergies in the brimonidine tartrate 0.2%/timolol maleate 0.5% group.

Discussion
Standard initial therapy for POAG patients is often a PGA.(10) However, when PGA therapy does not achieve adequate IOP control, there is no consensus for second-line therapy.
Typically, second-line treatment includes additional topical therapy (whether it be a single agent or combination drop) or a laser treatment. (14) Previous studies have compared laser treatments to single agent drops. (6,(9)(10)(11)(12) To the authors' knowledge, there has not been a study comparing laser procedures to combination medications as adjunct therapy in a headto-head trial. (6,(9)(10)(11)(12) The main finding from this single site, prospective, randomized, masked study, that compared SLT and brimonidine tartrate 0.2%/timolol maleate 0.5% as adjunct therapy in patients with uncontrolled POAG, was that both treatment groups demonstrated a statistically equivalent reduction in IOP. SLT lowered pressure 6.46 mm Hg (M = 28.43%, SD = .17) while patients that used drops achieved a 6.07 mm Hg reduction (M = 28.22%, SD = .12), t(21) = -.034. p = .973). This data suggests both SLT or brimonidine tartrate 0.2%/timolol maleate 0.5% are effective choices.
Though the results were statistically equivalent, there were several differences between the two treatments. SLT showed a larger effect size (d=1.86, large) than drops (d=1.50, large) but further analysis revealed that brimonidine tartrate 0.2%/timolol maleate 0.5% achieved a 20% or greater pressure reduction in 81.8% of patients compared to 58.3% with SLT.
However, neither the effect size or the 20% IOP reduction was statistically or clinically significant.
In a prospective randomized trial by Katz  concluded that baseline IOP is a significant indicator of SLT response and may explain why studies that had a higher baseline IOP achieved a greater IOP reduction with SLT (16) A study by Ayala and Chen also compared SLT as adjunct therapy for patients with openangle glaucoma or pseudoexfoliative glaucoma. Their study reported that patients receiving SLT as adjunct treatment to a PGA lowered IOP by 6.3 mm Hg (26.07%) while patients who were using a non-prostaglandin agent (Carbonic Anhydrase Inhibitor, Alpha-2 Agonist or Beta Blockers) had a similar 5.77 mm Hg (24.53%) reduction with SLT. (17) There was no statistically significant difference in IOP reduction between either group when SLT was added to patients using a PGA or non-prostaglandin agent. The current study showed a similar IOP percentage reduction to Ayala and Chen, despite difference in treatment protocol. Also, their cohort included a large percentage of patients with pseudoexfoliation (53.75%) while those patients were excluded in the current study.

Russo et al. compared Argon Laser Trabeculoplasty and 360 degree Selective Laser
Trabeculoplasty treatment as adjunct therapy in uncontrolled POAG patients on maximum medical management. They found that SLT achieved a 19.9% IOP reduction at one month, which is inferior to the IOP reduction of the current study. Since the early days of SLT, techniques have continued to be refined, and with the proper titration of laser energy, the safety profile of 360-degree SLT treatment is excellent as shown in the current study. (10,11) In keeping with the methodology of Katz et al., patients, not eyes, were randomized to receive either SLT or drops. This eliminated the possible concern of a crossover effect with topical medications, which was a criticism of the Glaucoma Laser Trial. (22,23) In the current study, patients that were treated with SLT were prescribed a topical antiinflammatory drop following the procedure, which was intended to help improve patient comfort during the postoperative period. Prednisolone acetate 1% four times a day for four days was selected based on a study performed by Relani et al., which showed no negative effect on IOP reduction at three months with this postoperative anti-inflammatory medicine.
A subgroup analysis of efficacy in the SLT arm showed a difference with respect to the amount of pigment in the trabecular meshwork. Pigment dependency could help explain the 15 variation in pressure reduction with SLT. In the current study, SLT therapy was found to be less effective in patients when the angle pigment was graded I or less. Pigment cells in the trabecular meshwork exhibit a greater optical absorbance of applied laser energy than non- SLT as compared to more heavily pigmented angles. Therefore, it may be reasonable to consider brimonidine tartrate 0.2%/timolol maleate 0.5%, which showed no obvious difference between angle pigmentation subgroups, before SLT as adjunct therapy for patients who have minimal to no angle pigment. Other factors such as the patient's preference, IOP reduction need, compliance, and cost considerations will ultimately influence the final decision.
SLT has proven to be a safe treatment for glaucoma. (6,9,10,(27)(28)(29) Major complications are rare and usually do not require any further surgical intervention. (6,10,(27)(28)(29) In the current study, only one patient (8.6%) in the laser group had a transient IOP spike that resolved in the office with the appropriate topical IOP drops. No major complications or adverse events associated with SLT such as iritis, hyphema, macular edema, or corneal edema were observed in the study. This study demonstrated that the efficacy and complication rates of SLT when performed by optometrists at this single site are comparable to the rates previously published in the literature. Additionally, the current and previous studies have shown that SLT is a viable option for both initial and adjunct therapy for the treatment of POAG. (6,(9)(10)(11) Not only does SLT lower IOP, but also it provides better patient compliance and adherence and may be more cost effective than topical drops. (3,32) SLT has been shown to reduce the nocturnal mean IOP and may blunt the nocturnal peak IOP.(33, 34) Possible limitations of the current study include its' small sample size, single study site, and short follow-up period. Although the follow up for the current study is short, a previous study showed that intraocular pressure remains stable at six months; therefore, one month values may be predictive of future intraocular pressure control. (9,17,19) The authors suggest that the results of the current study be confirmed with a larger multicenter randomized prospective trial that includes different glaucoma subtypes, a longer follow up period, and a more diverse patient population.

Conclusion
In conclusion, SLT and brimonidine tartrate 0.2%/timolol maleate 0.5% have been shown to be equivalent in lowering intraocular pressure in uncontrolled POAG patients when used as adjunct therapy for patients already taking a PGA Additionally, this is the first prospective study of optometrists performing SLT. Although this study had a small sample size, the results appeared to show that efficacy and complication rates were comparable to previously published data; however, these results need to be confirmed with a larger multicentered trial.

Declarations
Ethics approval and consent to participate: The study was conducted in accordance with all the ethical principles outlined by the Declaration of Helsinki and was approved by the institutional review board at the University of Pikeville. All subjects signed an informed consent prior to participating in the study.
18 Consent for publication: Informed consent also included notice of the possibility of publication.
Availability of data and material : The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.