Design and Baseline Characteristics of Participants in the Clarifying the Optimal Application of Selective Laser Trabeculoplasty (SLT) Therapy (COAST) Trial 1

Purpose

To describe the hypothesis and methodology for the ongoing Clarifying the Optimal Application of Selective Laser Trabeculoplasty (SLT) Therapy (COAST) trial 1 and participants’ baseline characteristics.

Methods

COAST Trial 1 is a multicenter randomized trial comparing standard-energy versus low-energy SLT as initial therapy for newly-diagnosed ocular hypertension (OHT) or mild-moderate primary open-angle glaucoma (POAG). The hypothesis is that 12-month survival following low energy SLT will be non-inferior to 12-month survival with standard energy SLT.

Results

When enrollment ceased, 418 participants had been randomized to low-energy (n=203) or standard-energy (n=215) SLT. Demographic and clinical characteristics were similar between groups. Most participants were White (66.5% and 67.9%, respectively) or Black/African American (25.1% and 21.4%, respectively). Qualifying diagnoses were mild POAG (59.6% and 62.1%, respectively), ocular hypertension (32.8% and 30.5%) and moderate POAG (7.6% and 7.4%). Mean optical coherence tomography retinal nerve fiber layer thickness was 81.9 and 82.0 μm, respectively; mean visual field mean deviation was −1.6 dB in both groups. Mean baseline IOP was highest among eyes with ocular hypertension (24.5 and 24.4 mmHg, respectively) and lower in eyes with mild (21.8 and 21.4 mmHg) and moderate POAG (22.0 and 21.0 mmHg).

Conclusions

COAST is a timely and potentially highly impactful trial that will clarify the optimal utilization of SLT for long-term glaucoma management without the need for alternative therapies such as medications or surgery. The COAST sample closely resembles the population of newly-diagnosed POAG/OHT patients for whom primary SLT would be appropriate, optimizing generalizability of study results when available.

Precis

COAST was designed to investigate alternate approaches to SLT to provide more effective long-term disease control without the need for alternate therapies such as medications or surgery. Methodology and baseline participant characteristics are described.

INTRODUCTION

After more than 150 years of a medication-first approach to glaucoma management, the therapeutic paradigm is in evolution. Many factors are contributory to this shift in approach. Among the most important is the recognition that self-administered topical medical therapy has important limitations including poor adherence^1–5 leading to higher progression risk^1,2,6,7 and a high incidence of side effects including chronic ocular surface disease in 30-80% of patients^8–14 that further disincentivizes adherence. Also, new therapeutic options—including selective laser trabeculoplasty (SLT), sustained drug delivery platforms, and minimally invasive glaucoma surgeries (MIGS)—have been developed that offer safe and effective intraocular pressure (IOP) reduction while obviating the need for daily topical medication self-dosing and thus overcoming its known limitations.

The landmark Laser in Glaucoma and Ocular Hypertension Trial (LiGHT) recently demonstrated that primary SLT decreased the risk of glaucoma progression and the need for both glaucoma and cataract surgeries more effectively than primary medical therapy in patients with newly-diagnosed and treatment-naïve ocular hypertension (OHT) or mild-moderate primary open-angle glaucoma (POAG).^15,16 Consequently, primary SLT has become the leading contender for first-line therapy in the new glaucoma treatment paradigm.^17–19

SLT was first described by Latina and colleagues more than 25 years ago and has undergone little modification in technique since its commercialization. More recently, some investigators have advocated for higher energy (either per shot or overall total energy)^20–24 and others for lower energy,^25–27 all with mixed results. The ongoing Clarifying the Optimal Application of SLT Therapy (COAST) trial was designed to identify the optimal energy and retreatment interval in patients with newly-diagnosed OHT or mild-moderate POAG with no or only brief prior exposure to topical medical therapy. COAST was designed as a pair of sequential randomized trials to compare the effectiveness of initial standard energy (titrated to fine cavitation bubbles) versus low-energy (0.4 mJ) SLT (Trial 1) and to compare two repeat SLT strategies—as-needed at standard energy (the current standard of care) versus annually at low energy irrespective of IOP—for long-term IOP control (Trial 2). The rationale for the trial’s design and the selection of treatment arms has been described previously²⁸ and recognizes that standard SLT produces damage to the trabecular meshwork^29–33 that is likely cumulative with retreatment and may limit the number of times SLT can be repeated before it ceases to be effective (the point of SLT exhaustion), while low-energy SLT likely produces less TM damage^32,34 and several small studies^25,26,35 have suggested it may be as effective as standard energy SLT in lowering IOP.

COAST was designed to answer the broad question: can the SLT procedure be optimized to provide more effective long-term disease control without the need for alternate therapies such as medications or surgery? COAST consists of two sequential trials: the first focuses on initial SLT therapy, and the second on repeat SLT therapy. Herein we describe the study design of Trial 1 comparing low-energy to standard-energy SLT as initial therapy for OHT and mild-moderate POAG and present the baseline characteristics of study participants.

METHODS

Study Design

COAST Trial 1 was a prospective, randomized, parallel-arm, active-controlled trial conducted at 28 centers in the United States and 1 center in Canada. The COAST study is funded by the United States National Institutes of Health/National Eye Institute (NIH/NEI) via grants to the Office of the Study Chair (OSC) at West Virginia University (UG1EY031654) and the Coordinating Center (CC) at the University of Pittsburgh (UG1EY031651). The study is overseen by a single institutional review board (IRB)—the WGC IRB—to which each site’s local IRB has ceded authority via institutional reliance agreements where applicable. Ethics approval was obtained at all sites, and all participants provided written informed consent before participation. In addition to the OSC, CC, and IRB, the study organization includes a steering committee, an independent data and safety monitoring committee (DSMC), an independent medical monitor, and representatives from the NIH/NEI.

Site Selection

The opportunity to participate as a COAST clinical site was broadcast via the American Glaucoma Society’s listserve discussion board as well as via the communications platforms of various ophthalmology organizations and trade publications. A web-based site application form collected information on clinical volumes, expected enrollment volumes, ability to recruit Black and Hispanic patients who are disproportionately affected by glaucoma,³⁶ prior research experience, current and recent clinical trial experience including success in meeting enrollment targets, and availability of experienced study coordinator support. Applications were scored and ranked by an independent panel selected by the NIH/NEI and the highest-ranking centers were invited to participate. Training of site personnel on study protocol and procedures was conducted remotely due to the COVID19 pandemic, and certification on both the protocol and study procedures was required before site activation.

Eligibility Criteria

Eligibility criteria are given in Table 1. Eligible participants were adults over age 18 years with best-corrected visual acuity (BCVA) of 20/200 or better in each eye and diagnosed with ocular hypertension or mild-moderate POAG. Both eyes were required to have one of the qualifying diagnoses but they could differ between eyes to permit enrollment of patients with asymmetric disease. Initially patients were required to be naïve to all topical IOP-lowering medical therapy; the protocol was revised to allow enrollment of participants with ≤6 months of cumulative therapy in the preceding 5 years. Key exclusion criteria included prior IOP-lowering laser or surgical procedures (with the exception of prophylactic laser iridotomy which was not exclusionary), advanced POAG (visual field mean deviation worse than −12 decibels or more than one test location within the central 5° with retinal sensitivity <15 decibels), glaucoma other than POAG, IOP >35 mmHg, and narrow or closed iridocorneal angles. There was no minimum IOP required for eligibility.

Table 1.

Eligibility criteria.

Inclusion Criteria
Age 18 years or older
Good general health
BCVA 20/200 or better bilaterally
One of the following qualifying diagnoses in each eye (can differ between eyes):	Ocular hypertension (IOP > 21 mmHg without glaucomatous optic neuropathy [GON] defined as excavation, diffuse or focal thinning or notching of the neuroretinal rim, visible nerve fiber layer defects, or asymmetry of the vertical cup-to-disc ratio of ≥0.2 between eyes)
	Mild POAG (GON and visual field mean deviation better than −6.0 dB with none of the four central 5° test locations having retinal sensitivity <15 dB)
	Moderate POAG (GON and either mean deviation between −6.0 and −12.0 dB inclusive with no central 5° test locations having retinal sensitivity <15 dB or mean deviation −12.0 dB or better with one 5° test locations having retinal sensitivity <15 dB)
Exclusion Criteria
Use of topical IOP-lowering medications for >6 months in the past 5 years
IOP-lowering laser or surgery (excluding prophylactic iridotomy)
Advanced POAG or other forms of glaucoma
Mean IOP >35 mmHg at eligibility or baseline visit
Narrow or closed iridocorneal angle (Shaffer grade 0-2)
Contraindications to study interventions
Corneal pathology precluding accurate Goldmann tonometry
Inability to attend all study visits
Pregnant or planning to become pregnant during study period

BCVA = best-corrected visual acuity, dB = decibel, GON = glaucomatous optic neuropathy, IOP = intraocular pressure, POAG = primary open-angle glaucoma

Visits and Assessments

The schedule of assessments and procedures is given in Supplementary Table 1. Potential participants underwent a comprehensive eye examination including gonioscopy, automated perimetry and optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) at an eligibility visit. IOP was measured using Goldmann tonometry and a two-person operator/recorder method as in prior trials.^37,38 The mean of two measurements (or three if the first 2 differed by ≥4 mmHg) was used for analysis. Visual fields were assessed using the Humphrey Field Analyzer and the SITA-standard 24-2 algorithm. Those meeting eligibility criteria attended a baseline visit at which baseline IOP and visual field were established. Qualifying diagnoses were based on the visual field performed at the baseline visit. If applicable, washout of IOP-lowering medications took place between the eligibility and baseline visits according to the following schedule: 4 weeks for prostaglandin analogues, beta-blockers, and rho kinase inhibitors; 2 weeks for alpha adrenergic agonists; and 5 days for carbonic anhydrase inhibitors and miotics; with fixed combinations based on component with the longest washout. Those still meeting eligibility criteria were randomly assigned in a 1:1 ratio to receive initial SLT at either standard energy or low energy. All eyes were pretreated with investigators’ preferred agent to prevent post-treatment IOP elevations. After the procedure, IOP, pain, and anterior segment examination were assessed 1 hour later. The use of anti-inflammatory therapy was at each investigator’s discretion. Post-treatment evaluations then took place 1, 4, 8, and 12 months later.

Randomization and Study Treatments

Randomization was at the participant level and both eyes received the same treatment. Randomization was blocked (2 or 4 per block) and stratified by site and diagnosis (in the eye with the higher mean IOP, or right eye if equal) and was accomplished using a predetermined sequence reported via a web-based data management system, or backup envelopes in special cases (envelopes were prepared using a similar but separate randomization table). Standard energy SLT consisted of 100 treatment spots throughout the full 360° beginning at 0.8 millijoules (mJ) and titrating energy up or down until fine champagne-like cavitation bubbles were visualized with every 2^nd or 3^rd shot. Energy was titrated throughout the procedure, in response to variations in pigmentation, to ensure the appearance of champagne bubbles with every 2^nd or 3^rd spot throughout the full 360° treatment. Energy was increased if no bubbles were seen with 5 consecutive spots and decreased if bubbles were seen with 5 consecutive spots. Low energy SLT consisted of 100 treatment spots delivered at 0.4 mJ per spot throughout the full 360° treatment, with the exception that energy could be reduced to 0.3 mJ if bubbles were seen with 5 consecutive spots (and was increased back to a maximum of 0.4 mJ if no bubbles were seen with 5 consecutive spots) or if pain was reported.

Target IOP, Retreatment Criteria, and Discontinuation of Therapy

At the end of the baseline visit (and after washout if applicable), a target IOP was established for each eye based on its qualifying diagnosis as follows: for OHT, a 20% reduction from baseline IOP; for mild POAG, a 25% reduction from baseline IOP and <21 mmHg; and for moderate POAG, a 25% reduction from baseline IOP and <18 mmHg. If IOP exceeded target IOP by >2 mmHg on two consecutive visits in either eye, SLT was considered to have failed and was repeated in that eye. The 2-mmHg margin was selected in recognition that minimal elevations above target IOP are often observed rather than treated in clinical practice. SLT could be repeated no more than once within a 12-month period. If retreatment criteria were met but SLT had already been performed twice within the preceding 12 months, the eye was considered to have reached the point of SLT exhaustion and study treatment was discontinued. Participants experiencing SLT exhaustion received non-study treatment at investigators’ discretion and attended all scheduled study visits through Month 12. If only one eye reached exhaustion and then received unilateral non-study therapy, the potential crossover effects could confound assessment of SLT effects in the fellow eye;³⁹ for this reason, discontinuation was a participant-level event whether one or both eyes reached SLT exhaustion. Also, if non-study IOP-lowering therapies were initiated in either eye for any other reason (e.g., by a non-study provider), participants were discontinued from study treatment.

Glaucoma Progression

The Humphrey Guided Progression Analysis (GPA) will be used to identify functional visual field progression. This program requires a minimum of five tests (two baseline and three follow-up) to detect likely progression, which is the study’s definition of functional progression. Likely progression is a determination reported by the GPA based on thresholds established in the Early Manifest Glaucoma Trial and occurs when three or more points show statistically significant worsening on three consecutive tests following two baseline tests.⁴⁰ Automated perimetry was performed at the eligibility and baseline visits and is repeated annually, with any changes confirmed with prompt retesting. Structural progression was defined as a ≥10 μm reduction from baseline in average OCT RNFL thickness on two consecutive tests. OCT RNFL measurements were obtained at the eligibility visit and are repeated annually thereafter, with any changes confirmed with prompt retesting. All commercially available OCT platforms were permitted across sites; sites with multiple platforms were asked to maintain consistency of platform within subjects throughout the study. Additionally, progression could be declared at investigators’ discretion if corresponding functional and structural changes not meeting the predefined thresholds on their own indicated worsening glaucoma. Progression was not considered a study endpoint. However, progression prompted a reduction in target IOP by 20% from the mean of up to the three most recent IOP measurements since the last SLT treatment if lower than the current target IOP. Quality guidelines were established for each test. Visual fields are acceptable if false positives, false negatives, and fixation losses are ≤33%; however less reliable tests are acceptable if the site investigator feels that the test reflects the participant’s visual field and that repeat testing is unlikely to improve quality. OCT quality thresholds are platform-specific: Heidelberg Q value ≥20, Cirrus signal strength ≥6, and OptoVue signal score index >28. Glaucoma progression was not expected to occur during COAST Trial 1 due both to the short timeframe of the study and to the frequency of testing; progression criteria were established to detect progression during the entirely of COAST study participation, which totals four years across Trials 1 (12 months) and 2 (36 months).

Safety Monitoring

All adverse events (AEs) were recorded, severity graded as mild/moderate/severe, and seriousness assessed. For serious adverse events (SAEs), relatedness to study intervention (unrelated/unlikely/possibly/probably/definitely related) as well as expectedness (yes/no) were also assessed. All AEs including SAEs were required to be reported to the coordinating center, and SAEs also to the IRB, within 1 working day of awareness. All SAEs were then reviewed by an independent medical monitor who reviewed sites’ assessments and made the final determination regarding severity, relatedness, and expectedness, after which unexpected and related SAEs were reported to the WCG IRB and DSMC within 1 day. Non-serious AEs were reported biannually to the DSMC.

Sample Size and Statistical Plan

The primary efficacy endpoint of COAST trial 1 is the success of initial SLT defined as achieving and maintaining target IOP through 12 months without the need for retreatment. A time-to-event analysis was developed with the hypothesis being that 12-month survival following low energy SLT will be non-inferior to 12-month survival with standard energy SLT. A 12-month survival of 85% was assumed for standard energy SLT based on prior studies;^16,41 a hazard ratio of 1.33 (corresponding to a 12-month survival rate of ~75% in the low energy SLT group) was selected as the margin of non-inferiority. To achieve 90% power for a log-rank test comparing the two Kaplan-Meier curves with a one-sided alternate hypothesis at the 2.5% significance level, a sample size of 542 participants is required. This sample size of analyzable participants was then adjusted both for a 3.5% anticipated attrition rate in the first year as well as an inflation to account for paired eyes from each participant. A design effect (DE=1 + (m-1) ρ) was used to estimate the sample size based on the assumption of independent participants, resulting in a total sample of eyes, where m is the cluster size (m=2), and ρ is the intra-eye correlation in each cluster which was estimated to be 0.7 based on the LiGHT study (Gus Gazzard, personal communication). Given that each participant contributes two eyes to the analysis, the effective sample size was adjusted for the design effect of 1.7 eyes per participant to account for the correlation between paired observations. Considering the design effect and the anticipated attrition rate, a total of 1,276 eyes of 638 randomized participants was the final sample size required.

The primary analysis will be conducted in the intention-to-treat population of all randomized participants with at least one on-treatment assessment. The primary analysis will be based on a shared frailty model in which the cluster effects are incorporated into the Cox proportional hazard model as independent and identically distributed random variables to account for the within-cluster correlation.

In this paper, the baseline characteristics of participants are described by treatment group. Continuous variables are described by their means and standard deviations, and categorical variables are described as frequency distributions and proportions.

A planned interim analysis of the primary outcome was conducted when 25% of the sample reached the 12-month time point and revealed a statistically significant difference between groups. Based on recommendation by the DSMC and the NIH/NEI, the trial was stopped early after 418 participants had been randomized. Final Trial 1 results will be reported separately once all randomized and treated participants complete the 12-month trial.

RESULTS

Overall, 550 potential participants were screened and 418 participants were randomized (203 to low energy SLT and 215 to standard energy SLT). The baseline participant-level characteristics of the study sample by treatment group are given in Table 2 and were well balanced between groups. The mean (standard deviation) ages of participants in the low energy and standard energy groups were 62.3 (12.9) and 62.7 (11.4) years, respectively. Approximately two-thirds of the participants were White (66.5% and 67.9%, respectively), with Black/African American participants representing most of the remaining participants (25.1% and 21.4%, respectively). The groups included 8.4% and 8.8% Hispanic participants, respectively.

Table 2.

Baseline participant-level demographic data of the study sample by treatment group.

	Low Energy SLT (N=203)	Standard Energy SLT (N=215)
Age (yr), mean (SD)	62.3 (12.9)	62.7 (11.4)
Race, n (%)
White	135 (66.5)	146 (67.9)
Black or African American	51 (25.1)	46 (21.4)
Asian	4 (2.0)	8 (3.7)
Other/Declined	13 (6.4)	15 (7.0)
Ethnicity, n (%)
Hispanic or Latino	17 (8.4)	19 (8.8)
Not Hispanic or Latino	179 (88.2)	189 (87.9)
Declined to answer	7 (3.4)	7 (3.3)
Sex, n (%)
Female	117 (57.6)	118 (54.9)
Male	86 (42.4)	97 (45.1)

SD = standard deviation, SLT = selective laser trabeculoplasty

The baseline eye-level glaucoma clinical characteristics of the study sample are given in Table 3 and were also well balanced between groups. Most eyes in both the low energy and standard energy groups had mild POAG (59.6% and 62.1%, respectively), with ocular hypertension (32.8% and 30.5%, respectively) and moderate POAG (7.6% and 7.4%, respectively) making up the remainder. This was reflected in both the baseline structural and functional glaucoma parameters, including mean vertical cup-disc ratio (0.6 in both group), mean OCT RNFL thickness (81.9 and 82.0 μm, respectively), and mean visual field mean deviation (−1.6 dB in both groups). The qualifying diagnosis was symmetrical between fellow eyes in 82.3% of participants. Only 20 eyes (10 in each group) underwent washout of IOP-lowering medications prior to the baseline visit.

Table 3.

Baseline eye-level glaucoma clinical characteristics of the study sample by treatment group.

	Low Energy SLT (N=203)	Standard Energy SLT (N=215)
Age (yr), mean (SD)	62.3 (12.9)	62.7 (11.4)
Race, n (%)
White	135 (66.5)	146 (67.9)
Black or African American	51 (25.1)	46 (21.4)
Asian	4 (2.0)	8 (3.7)
Other/Declined	13 (6.4)	15 (7.0)
Ethnicity, n (%)
Hispanic or Latino	17 (8.4)	19 (8.8)
Not Hispanic or Latino	179 (88.2)	189 (87.9)
Declined to answer	7 (3.4)	7 (3.3)
Sex, n (%)
Female	117 (57.6)	118 (54.9)
Male	86 (42.4)	97 (45.1)

dB = decibels, OCT RNFL = optical coherence tomography retinal nerve fiber layer, POAG = primary open-angle glaucoma, SD = standard deviation, SLT = selective laser trabeculoplasty

The baseline IOP data are given in Table 4 and Figure 1. Mean baseline IOP was highest among eyes with ocular hypertension (24.5 and 24.4 mmHg in the low energy and standard energy groups, respectively), was 21.8 and 21.4 mmHg in eyes with mild POAG, and was 22.0 and 21.0 mmHg in eyes with moderate POAG. Correspondingly, mean target IOP was higher in eyes with ocular hypertension (19.4 and 19.5 mmHg, respectively) than eyes with mild (16.1 and 15.9 mmHg, respectively) or moderate POAG (15.7 and 15.1 mmHg, respectively).

Table 4.

Eye-level baseline and target IOP (mmHg) by qualifying diagnosis for each treatment group.

	OHT (N=264)		Mild POAG (N=509)		Moderate POAG (N=63)
	Low Energy (N=133)	Standard Energy (N=131)	Low Energy (N=242)	Standard Energy (N=267)	Low Energy (N=31)	Standard Energy (N=32)
Baseline IOP, mean (SD)	24.5 (4.0)	24.4 (3.0)	21.8 (4.6)	21.4 (4.2)	22.0 (5.0)	21.0 (5.6)
Target IOP, mean (SD)	19.4 (2.7)	19.5 (2.3)	16.1 (2.9)	15.9 (2.9)	15.7 (2.8)	15.1 (3.4)

IOP = intraocular pressure, OHT = ocular hypertension, POAG = primary open-angle glaucoma, SD = standard deviation

Figure 1.

Baseline intraocular pressure (IOP) by treatment group and qualifying diagnosis. Boxes represent the central 50% of values, central lines represent median values, vertical lines represent ranges, and single points represent outlying values. OHT = ocular hypertension, POAG = primary open-angle glaucoma.

DISCUSSION

The glaucoma treatment paradigm is in evolution. The recent LiGHT trial has compellingly demonstrated that primary SLT is more effective than medications in preventing both disease progression and the need for subsequent glaucoma surgery (although the latter may have been driven by design features that favored surgery as next-step therapy in medication-treated eyes).^15,16 The results of LiGHT are likely driven by adherence issues which are known to limit the effectiveness of topical medical therapy,^1–5 as SLT eliminates the need for daily self-administration of medical therapy and thus eliminates nonadherence with such therapy. SLT has other important benefits over medical therapy, including a more favorable safety profile and superior cost-effectiveness.^{15,16,42–45} The shift to an SLT-first approach to glaucoma therapy is underway. Following guidance from the National Institute for Health and Care Excellence, the United Kingdom’s National Health Service now positions SLT as the preferred first-line therapy for patients with newly diagnosed POAG/OHT.¹⁷ Likewise, the American Academy of Ophthalmology’s Preferred Practice Pattern for Primary Open-Angle Glaucoma has revised its recommendations for SLT use, from “…laser trabeculoplasty is an alternative for patients who cannot or will not use medications…” (2005⁴⁶) to “…can be considered as initial therapy in select patients…” (2010,⁴⁷ 2016⁴⁸) to “…may be used as initial or adjunctive therapy in patients with POAG…” (2020¹⁸).

A pair of real-world studies of SLT have demonstrated less impressive outcomes than those seen in the LiGHT trial.^49,50 In the study by Khawaja and colleagues,⁵⁰ a median survival time of 1.35 years was reported in eyes undergoing primary SLT. This is substantially less than the >6-year median survival time of primary SLT in the LiGHT study.¹⁵ However, these studies differ from LiGHT (and COAST) in several important ways. In the study by Abe and colleagues,⁴⁹ 84% of participants received SLT adjunctively to medications rather than as primary therapy (and the 16% undergoing primary SLT were not analyzed/reported separately), 11% received <360 degree treatment, and the baseline IOP was 18.4 mmHg, substantially lower than the 24.5 mmHg baseline IOP in SLT-treated eyes in LiGHT. The lower baseline IOP leaves a much smaller therapeutic window for SLT to demonstrate efficacy. Also, the very nature of adjunctive SLT is that it is used in the subset of eyes that are recalcitrant to treatment and require more than medications for adequate IOP control; higher failure rates would be expected. Further, the inclusion of medically-treated eyes is important because there is evidence that chronic medical therapy induces histological changes in ocular structures including the trabecular meshwork that may render it less responsive to SLT compared to medication-naïve eyes.^51–53 In both studies, data were collected retrospectively, no information on mean laser energy were provided, systematic assignment of target IOP was not described (and presumably not utilized), and there was no mention that IOP was measured more than once at each visit to minimize measurement errors. This latter point is important because in both studies, intensification of glaucoma therapy was considered a failure criterion and there was no standardization of the application of intensification of glaucoma treatment. Without multiple measurements at each time point and the requirement to confirm elevated IOP at a second visit before intensifying therapy, measurement error or spontaneous IOP variability may have led to early and unnecessary treatment intensification. Thus, many of the treatment failures in both of these real-world studies might have been avoided had the robust design of LiGHT (and COAST) been applied. It is for these reasons that real-world studies rarely reproduce trial results—they are not robust. Because of these important methodological differences, the dissimilarities in these two real-world studies’ outcomes compared to LiGHT in no way diminish the impact of LiGHT’s findings in medication-naïve eyes.

The COAST trial is a timely investigation of optimal SLT technique just as the procedure is becoming the preferred primary treatment option for newly-diagnosed glaucoma and its utilization is increasing. Since its initial description by Latina and colleagues in 1998,⁵⁴ there has been much interest in modifications to the SLT procedure, especially with regard to the optimal energy to be used. The energy level utilized in the pilot trial by Latina and colleagues was selected based on laser energy absorption characteristics observed in cultured TM cells^54,55 and is commonly used in clinical practice today. Both higher energy (either per shot or overall total energy)^20–24 and lower energy^25–27 have been advocated, although well-designed and adequately-powered multicenter trials to evaluate these approaches have been lacking. A recent randomized trial conducted in Sweden compared two SLT energy levels that approximate the treatment arms in COAST Trial 1 and found that higher energy more effectively provided superior IOP reduction and longer duration of IOP control than lower energy in achieving and maintaining target IOP.²³ The study sample for that trial differed significantly from COAST’s in that most participants in the Swedish trial received SLT as adjunctive therapy to medications, and many patients had previously undergone one or more prior SLT treatments at the time of study entry.

COAST was designed to answer the broad question: can the SLT procedure be optimized to provide more effective long-term disease control without the need for alternate therapies such as medications or surgery? To maximize the combined impact of the two largest SLT studies conducted to date, key aspects of the LiGHT study design were harmonized in COAST’s design, including eligibility criteria, target IOP determination, and the treat-in-pursuit-of-target approach.⁵⁶

Considerable effort was made to optimize the applicability of COAST results to the broadest possible population of patients with OHT/POAG requiring initial therapy. Unlike prior studies evaluating different SLT energy levels,²³ we restricted study entry to patients who were SLT-naïve and largely medication-naïve as well to best characterize SLT’s role as initial therapy. We elected not to enroll patients who had received chronic topical medical therapy (>6 months), because there is some evidence that chronic medical therapy might adversely affect trabecular meshwork (TM) cellular health.^51–53 If this were the case, SLT—which targets the TM—may have a different efficacy and safety profile in previously treated versus treatment-naïve eyes, and results seen in patients washed out from chronic topical medical therapy may not generalize to medication-naïve patients.

Additionally, recognizing that glaucoma disproportionately affects Black and Hispanic people,³⁶ we incorporated strategies to ensure that at least 25% of the study sample was non-White. These strategies included specific queries regarding Black and Hispanic enrollment potential on the site application, a factor that was weighted significantly in the site selection process, as well as outreach to practices in areas with large Black and Hispanic populations to request that they consider applying to be a COAST study site. These efforts were successful, as >32% of the Trial 1 study sample self-identified as non-White or Hispanic.

The eligibility criteria were modified shortly after the trial began to ensure broader generalizability of study results. Initially, only treatment-naïve patients were eligible to participate. Feedback from site investigators revealed that many patients receive initial diagnoses in outside practices and are started on topical therapy for temporary IOP control and referred to tertiary care centers for definitive diagnosis and treatment. Under the first version of the protocol, these patients were ineligible to participate in COAST because they were not strictly treatment-naïve, posing two important consequences: first, a missed opportunity to enroll otherwise eligible patients with minimal exposure to medical therapy, and second, the possibility that the private practice COAST sites and the academic COAST sites may enroll participants from different patient populations. The eligibility criteria were modified to permit enrollment of patients who had received no more than 6 cumulative months of topical therapy within the five years preceding study entry, provided they underwent washout of all topical therapy before the baseline visit; this was felt to adequately balance the competing goals of facilitating enrollment and minimizing the potential effects of prior medical treatment on study outcomes. As a result of these efforts, we believe that the COAST sample closely resembles the population of newly-diagnosed POAG/OHT patients, optimizing generalizability of study results when available.

When evaluating a potential new standard for first-line therapy, safety monitoring is an important aspect of study design. We developed a robust multi-level assessment program to evaluate all adverse events, including serious adverse events, to ensure that safety issues were promptly identified and addressed if needed. This system included a medical monitor to ensure accuracy and consistency of SAE reporting across sites and a DSMC to consider the potential impact of both safety and efficacy data on study conduct and recommend modifications to the protocol or processes as needed. We also developed a process for identifying and responding to glaucoma progression during the trial. We standardized both structural and functional progression definitions but also included a subjective definition that permitted investigators to declare progression that fell short of standardized criteria. Because of the time and number of tests required to detect either functional or structural progression, neither could be detected within the 12-month period of Trial 1. However, as participants completing Trial 1 without discontinuation of study treatment were re-randomized into Trial 2 for an additional 36 months, both functional and structural progression will be detectable in Trial 2. Progression is not considered a treatment failure if it occurs in the absence of SLT retreatment criteria. However, progression does prompt a reduction in target IOP, which would be expected in most cases to lead to retreatment to attain the lower target IOP. This reflects common clinical practice, which was a key goal of COAST’s study design.

The global COVID19 pandemic had a significant impact on COAST during its first two years. COAST received funding in September 2020, at a time when many institutional research administration offices were understaffed and patients were reluctant to visit health centers unless absolutely necessary. Consequently, many of COAST’s start-up activities—including contracting, IRB approvals, and site training—exceeded their originally planned timelines. Also, once greenlighted for enrollment, many sites reported slower than expected participant recruitment as patients were unwilling to attend more than the minimum number of clinical visits to receive care. The COAST team took a multi-pronged approach to these issues. First, a second round of site selection/activation was undertaken to increase the number of active enrolling sites. Second, an outreach program was developed to assist site investigators in engaging community eye care providers to identify and refer potential participants to study sites. This program centered around a Referral Toolkit, which contained brochures for both referring providers and their patients, a video in which the study chair explained the purpose and goals of COAST and reviewed eligibility criteria, index cards printed with eligibility criteria for placement in examination rooms or coat pockets for easy reference, and direct contact information to local sites’ study coordinators to facilitate referrals. Third, the study chair also conducted a live webinar on the evolving glaucoma paradigm including an overview of COAST, a video recording of which was posted on the study website for site teams to share with their referring providers. A Referring Partners program was developed in which referring providers are recognized for their support with certificates and plaques signed by study leadership and NIH/NEI representatives to display in their offices. Cumulatively, these activities produced a rapid increase in enrollment consistently meeting projected monthly targets up to the point of early study completion.

Strengths of the COAST trial include many aspects of its design. First, its inclusion of treatment-naïve (or briefly treated and washed out) patients ensures generalizability of results to newly-diagnosed patients requiring treatment. Second, its sample includes a diverse representation of populations disproportionately affected by glaucoma. Third is its sequential-trial design. COAST is designed as a pair of sequential studies—the first evaluating initial therapy (trial 1) and the second evaluating repeat therapy (trial 2)—utilizing the same study sample by re-randomizing trial 1 completers into trial 2; the ability to answer two related but different clinical questions with a single study sample has optimized both efficiency and cost. Fourth is its timeliness, as the study evaluates a topic of great interest as SLT’s utilization is on the rise. A key limitation is the inclusion of only a single alternative to standard energy SLT as initial therapy and a single alternative strategy to as-needed repeat SLT for long-term disease control. However, the choice of treatment strategies in COAST was the result of an evidence-based review of the relevant lliterature.²⁸ Additionally, COAST did not specify a minimum baseline IOP as an entry criterion, as POAG occurs across the spectrum of IOP and any such minimum value would arbitrarily exclude a subset of patients and needlessly limit generalizability. This design aspect allows participants with low baseline IOP and thus low target IOP to be enrolled, and consequently some eyes could theoretically have a target IOP lower than would reasonably be expected to be achieved with SLT. However, investigators were instructed to enroll participants only if they believed that SLT would be capable of achieving assigned target IOP.

In summary, COAST Trial 1 compares low versus standard energy SLT as initial therapy for ocular hypertension and mild-moderate POAG. The trial has completed enrollment and is ongoing; final results will be reported upon completion of the trial. Participants who successfully complete Trial 1 are randomized into Trial 2, which compares long-term IOP control with SLT repeated as needed at standard energy (the current standard of care) versus SLT repeated annually at low energy irrespective of IOP to maintain TM health and function. Details of Trial 2 will be reported separately. COAST is a timely and potentially highly impactful trial that will clarify the optimal utilization of SLT for long-term glaucoma management without the need for alternative therapies such as medications or surgery.

COAST Publications Author List

CLINICAL SITES (alphabetical order):

Chicago Arbor Eye Institute

PI: Richard Quinones

Co-Investigator: Shelby Rogers

Coordinators: Lorene Rafol

Technicians: Mandy Masters and Kiersten Schell

Clear Vue Laser Eye Center

PI: Monique Barbour

Coordinators: Michelle Hill and Bria George

Cleveland Clinic Cole Eye Institute

PI: Ang Li

Co-Investigators: Rupak Dhoot, Jonathan Eisengart, Vishal Patel and Daniel Petkovsek

Coordinators: Pam Donati, Theresa Kovacs, Nicole Shepherd, Thais Silva and Dusica Vasic

Other: Anna Asik, Briana Benson, Stephanie Burke, Megan Cidor, Catherine Cox, Katelynn Greer, Jonelle Hairston, Mark Harrod, Victoria Hawk, Morgan Jackson, Lisa Jahn, Andrea Mask, Angela Meador, Zachary Morales, Mary Ann Peppard, Rachel Posey, Rachel Rusnak, Markeba Stephens, Deja Stewart and Jackson Winans

Devers Eye Institute

PI: Robert Kinast and Jonathan Young

Coordinators: Cindy Albert, Jack Rees and Michael Shaw

Others: Paul Newton and Angie Urrutia

Doheny Eye Center UCLA

PI: Judy Chen

Co-Investigator: Stephanie Midtling

Coordinators: Karina Lozano and Mayra Raygoza

Others: NaMee Donan and Janett Mendez

Eye Care Specialists

PI: Daniel Lutz

Co-Investigators: Carrie Cardillo and Michael Fasano

Coordinators: Cheryl Bayley, Melissa Horvath, Lauren Kilduff, Patti Myers and Patty Yuhas

Harvard Eye Associates

PI: Ye Elaine Wang

Coordinator: Jasmin Kaur

Others: Tina Duong, Yerin Kang, Jarred Metkus, Andrea Mihailescu and Lannhi Nguyen

Illinois Eye Center

PI: Sachin Kalarn

Co-investigators: Evan Lagouros and Patrick Rhode

Coordinators: Lori Hendershott and Nicole McDonald

Others: Angela Bristol, Jessica Burress, Miranda Clardy, Jessica Ewalt, Linda Gentzen, Vicki Mahrt, Ryan Nelson, Melissa Peters, Jeremy Pickering, Stephanie Rhoads, Mindy Uppole, Yvonne Vest, Lita Williams and Krista Wynes

Kresge Eye Institute/Wayne State University

PI: Bret Hughes

Co-investigators: Mark Juzych and Xiaofan Mi

Coordinators: Bayan El-Haik and Cheryl Milanovic

Others: Sara Ash, Gregory Davis, Sabrina Garcia, Sue Grenstiner, Allison Koenke, Hailey Litzer, Melissa Machado, Constance McVeigh, Anita Riggs, Ashley Truchan and Anahli Vazquez-Galvan

Mark A. Latina. LLC

PI: Mark Latina

Coordinators: Ann Gardikas and Chantal McCarron

Massachusetts Eye and Ear Institute

PI: Michael Lin

Co-investigator: David Friedman

Coordinators: Kanza Aziz, Michael Cheung, Dagmawi Misgano and Matthew Stenerson

Others: Sofia De Arrigunaga, Sandra Freeman, Joyce Kang and Tony Succar

Mile High Eye Institute

PI: Zachary Vest

Co-investigators: Madeline Graber and Marshall Huang and Audrey Hudson

Coordinators: Michelle Lopez Galindo and Alicia Ortiz

Others: Kyle Claypool, Isaiah Cruz, Evelyn Garcia, Maya Garcia-DeHerrera, Erica Hernandez, Stephanie Saavedra and Rosemarie Vigil

New York Eye Surgery Associates

PI: Nathan Radcliffe

Coordinators: Krystina Tavarez-Feliciano and Gerard Scalera

Northwestern Medical Group

PI: Angelo Tanna

Co-Investigators: Alcina Lidder and Jessica Kang

Coordinators: Davis Bhagat, Alessandra Charles, Angela Giliana, Brianne Guzouskis, Keshav Jindal, Michell Kim, Ethan Miller, Rachel Moore, Komel Safdar, Sonia Sandoval, Madison Wood and Sarah Zaida

Others: Magali Barrera, Ashli Bielarz, Fatai Brown, Eglantina Diaz Flores, Sarah El-Habash, Aaron Espinoza, Tara Farmer, Khali Garland, Andrea Hopkins, Abby Hreha, Anson Moore, Marsha Oberbroeckling, Ana Paredes, Julie Pecht, Jaela Powell, Laura Quinonez, Alexi Ramos, Stephanie Ramos, Christina Rodriguez, Vanessa Rodriguez, Christina Sammour, Gabriela Slomicz and Kaitlyn Veto

Ocular Health Centre- Kitchener (Ontario, Canada)

PI: Tony Chan

Co-investigators: Monica Carrillo, Jaspreet Rayat and Richard Weinstein

Coordinators: Siham Al Saeed, Sandra Caballero, Nirmit Shah and Edward Tran

Ophthalmic Consultants of Boston

PI: Theodor Sauer

Co-Investigator: Husamuddin Ansari

Coordinators: Sandy Chong, Quinn Hogan, Tejinder Kaur, Jason Lu, Maria Jose Martinez Lopez and Sarina Pilek

Ophthalmology Associates

PI: Brian Flowers

Coordinators: Julia Allen, Jose Rosado, Kaitlin Sinclair and Kelly Starr

Other: Russ Hardin

Scheie Eye Institute at UPenn

PI: Ahmara Ross

Co-investigators: Victoria Addis, Qi Cui, Eydie Miller and Prithvi Sankar

Coordinators: Ellen Betterson, Devica Bhutani, Yuanyuan Chen, Joan DuPont, Naomi Hollo, Emma Iacobucci, Joshua Paulos and Criston Young

Others: James Berger, Andrew Billek, Shaka Draper, Xiaoshuang He, Kelsey Parchinski and Gabriela Slomicz

Spokane Eye Clinical Research

PI: Rory Allar

Co-investigators: Hari Bodhireddy and Steven Day

Coordinators: Wendy Black, Jessica Gauche, Brian Skea and Dylan Waidelich

UM Kellogg Eye Center

PI: Amanda Bicket

Co-Investigators: Denise John and Annie Wu

Coordinators: Lindsay Rudberg and Abby Sharp

Others: Pamela Campbell, Sonya Cosby, Tim Costello, Callie Gordon, Judith Gulian, Kristin Jones, Lianne Shami and Courtney Snyder

University Hospitals Eye Institute- Case Western

PI: Douglas Rhee

Co-investigators: Yasemin Sozeri and Kevin Donahue

Coordinators: Sangeetha Raghupathy, Leslie Richards, Rashad Spruill and Barbara-Georgeia Stephens

University of California, Davis

PI: James Brandt

Co-investigators: Judy Chen, Rebecca Chen, Michael Gale and Michele Lim

Coordinators: Marisa Arnold, Susan Garcia, Denise Macias, Leslie Valverde and Cynthia Wallace

Others: Megan Hughes-Salaber and Gregory Kizer

University of California, San Francisco (UCSF)

PI: Ying Han

Co-Investigators: Tiffany Chen, Jennifer Currier, Nicole Mercho and Sriranjani Padmanabhan and Jing Shan

Coordinators: Mari Costantini, Ashika Kuchhangi, Benjamin Liu, Jenny Lu and Patrick Takla

University of Pittsburgh Medical Center (UPMC)

PI: Ian Conner

Co-investigators: Tarek Shazly, John Swogger and Andrew Williams

Coordinators: Rhonda Dahlstrom, Peter Goralski, Sashan Morris and Dipanwita Samanta

Others: Natalie Anthony, Rose Carla Aubourg, Michael DeRosa and Chad Indermill

University of Wisconsin-Madison

PI: Yao Liu

Co-investigators: Katy Coggins, Elleny Gutierrez, Michal Gutowski, Gregg Heatley, Emerson Kendall and Anna Momont

Coordinators: Kelly Boyd and Christopher Smith

Others: Angie Adler and Jennie Perry-Raymond

Vanderbilt Eye Institute

PI: Rachel Kuchtey

Co-Investigators: Eric Brown, Sylvia Groth, Karen Joos, Reid Longmuir and Jeffrey Mattingly

Coordinators: Tony Adkins, Marybeth Carter, Crystal Nicholson, Lindsay Veach and Saige Wilkins

Others: Magda Hanna, Ilissa Manning, G. Rocky Munn, Richard Skellie and Sandy Sok

West Virginia University Eye Institute

PI: Tony Realini

Co-investigators: Kevin Halenda and Brian McMillan

Coordinators: Athena Echols, Aimie Jones, Natalie London, Stefanie Philippi, Cassidy Pinion, Shannon Sampson, Allison Sisler and Charlene Sue Underwood

Wills Eye Hospital

PI: Lauren Hock and Daniel Lee

Co-Investigators: Dilru Amarasekera, Elizabeth Dale, Leangelo Hall, Teresa Horan, Ping Huang, Michael Izzo, Natasha Kolomeyer, Marlene Moster, Jonathan Myers, Rebecca Neustein, Reza Razeghinejad, Joel Schuman, Justin Shortell, Aakriti Shukla, Connie Wu and Tina Xia, Moon Jeong Lee, Sefy Paulose and Kevin R. Zhang

Coordinators: Meskerem Divers, Taylor Harwood, Jeanne Molineaux and Sheryl Wizov

Others: Lilian Nguyen and Megan O’Connell

Wilmer Eye Institute/Johns Hopkins

PI: Pradeep Ramulu

Co-investigators: Jella An, Mona Kaleem and Nathaniel Kheysin

Coordinators: Susmita Karan, Ala Novik, Rucha Thaker and Christine Zemsky

Other: Rhonda Miller

Other Groups (alphabetical order):

Coordinating Center, University of Pittsburgh

PI: Stephen Wisniewski and G.K. Balasubramani

Coordinators: Owomide Adeyemi, Mary Martinez, Scott O’Neal, Vicky Palombizio and Deidra Ressler Fricke

Others: Steve Barton, Kimberly Beringer, Pritika Dasgupta, Luke DiPalma, Heather Eng, Ping Guo, David Hallam, Tamara Haller, Michael Kania, Tanya Kenkre, Yulia Kushner, Deborah Martin, Jeff Martin, Caroline Morawski, Jeffrey O’Donnell, Chelle Pronko, Kathleen Stewart, Myla Stiegler, Alex Washy, Victor Washy, Allison Weller, Jenny Wolsk and Matthew Zourelias

DSMC Committee Members

Chair: Kevin Anstrom

Members: Benjamin Arnold, Eve Higginbotham, Steve Mansberger, Paula Anne Newman-Casey and Nicholas Evans

Medical Monitor

Robert Fechtner, Syracuse University

Office of the Study Chair, West Virginia University

Study Chair: Tony Realini

Coordinators: Athena Echols, Aimie Jones, Natalie London, Stefanie Philippi, Cassidy Pinion, Shannon Sampson, Allison Sisler and Charlene Sue Underwood

Other Steering Committee Members: Michael Kass, Washington University; Gus Gazzard, Moorfields Eye Hospital

Study Sponsor: National Eye Institute (NEI)

Donald Everett and Jimmy Le