Table 1.

Characteristics of included studies [ordered by study ID]

LoGTS 2011
Methods	Study design: parallel-group, randomized controlled trial. Number randomized (total and per group): 190 total participants randomized; number per group not reported Number analyzed (total and per group): Exclusions: 12 total participants randomized; number per group not reported Loss to follow up: at one year, 36/99 (36%) participants in brimonidine group and 8/79 (10%) participants in timolol group were lost to follow up; at four years, 54/99 (55%) participants in brimonidine group and 23/79 (29%) participants in timolol group were lost to follow up Study follow up: planned follow up was four years. Sample size calculation: 64 participants for 80% power to detect outcome differences between groups
Participants	Country: USA (13 clinical centers). Age (mean ± SD): 64.9 ± 10.7 years. Gender: women (n = 113; 59.5%) and men (n = 77; 40.5%). Inclusion criteria: “Men and women, ≥ 30 years of age, with previously diagnosed LPG. Untreated LPG with Goldmann applanation IOP ≤ 21 mmHg on a diurnal (8 AM, 10 AM, 12 PM, 4 PM) curve before medication randomization.” Exclusion criteria: “History of untreated IOP > 21 mmHg, or a > 4 mmHg difference in IOP between the eyes. Advanced visual field loss (mean deviation, > 15 dB) or threat to fixation. Corrected visual acuity < 20/40 in either eye. Pigmentary or exfoliative glaucoma. History of angle-closure or an occludable angle by gonioscopy. Prior filtration surgery or laser iridotomy. Cataract surgery with posterior chamber lens implant performed less than 1 year before enrollment. Argon laser trabeculoplasty performed less than 6 months previously or for an untreated IOP > 21 mmHg. History or signs of inflammatory eye disease, ocular trauma, or potentially progressive retinal disease. History of allergy or intolerance to topical timolol, brimonidine, or to any components of these medications. Resting pulse rate < 50 beats/minute. Severe, unstable, or uncontrolled cardiovascular, renal, or pulmonary disease. Women pregnant, nursing, or contemplating pregnancy.”
Interventions	Intervention 1: bilateral treatment with topical brimonidine 0.2% twice daily Intervention 2: bilateral treatment with topical timolol 0.5% twice daily. General procedures for all participants: topical ocular hypotensive medications were discontinued prior to study with appropriate washout periods; no other IOP-lowering agents were allowed during study period
Outcomes	Primary outcome, as defined in baseline paper: “Significant progression of the same two or more points, on the Humphrey glaucoma change probability maps or by Progressor linear regression analysis, in 3 consecutive (over an 8-month period) Humphrey 24-2 full threshold fields.” Primary outcome, as defined in results paper: “The primary outcome measure was visual field progression in either eye as determined by pointwise linear regression analysis of all study visual fields with Progressor software (Medisoft Inc., Leeds, UK).” Secondary outcome, as defined in results paper: “A secondary outcome was visual field progression in either eye evaluated by Humphrey glaucoma change probability maps (GCPM).” Other measurements taken at baseline and follow-up visits: “patient reported ocular and systemic events; measurement of blood pressure, pulse, best-corrected visual acuity, and IOP; slit-lamp examination; and optic disc evaluation for cup-to-disc ratio and the presence or the absence of disc hemorrhage. Gonioscopy and stereoscopic optic disc photographs are performed at yearly intervals. Humphrey achromatic visual fields (full-threshold 24-2 program) are performed according to protocol guidelines at 4-month intervals after randomization.” Measurements taken “every 4 months with visual fields and yearly optic disc photographs for a minimum of 4 years.” Unit of analysis: individual (patient-based).
Notes	Study dates: enrollment from June 1998 to August 2000. Funding source(s): Allergan, Inc (Irvine, CA); Chicago Center for Vision Research (Chicago, IL) Conflicts of interest: none reported. Publication language: English.
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“Participants were assigned to 1 of 2 treatment groups, brimonidine tartrate 0.2%or timolol maleate 0.5% (both medications used throughout the study), according to a computer-generated randomization list stratified by center.”
Allocation concealment (selection bias)	Low risk	“The randomization assignment list is maintained and masked study medications are provided directly to the clinical centers by Fountain Valley Pharmacy (Fountain Valley, CA). Optic disc, visual field, and coordinating centers are masked from each other. Data on treatment effects and the randomization code are not provided during the course of the study.”
Masking of participants and personnel (performance bias)	Low risk	“Full masking of patients, physicians, technicians, and the reading center for visual fields and optic disc photographs.”
Masking of outcome assessment (detection bias)	Low risk	“Full masking of patients, physicians, technicians, and the reading center for visual fields and optic disc photographs.” “Data Center for masked computer analysis of the visual fields.”
Incomplete outcome data (attrition bias) Exclusion of participants	High risk	“12 randomized patients were subsequently excluded (10 from withdraw of a study site, 1 withdrew consent, and 1 did not meet entry criteria).” “End points requiring withdrawal from the study include the following: (1) treated IOP of more than 21mmHg that is repeatable within 1 month; (2) visual field progression; (3) development of allergy or intolerance to the study medication; (4) clinical decision by the treating ophthalmologist that it is unsafe for the patient to continue in the study.”
Incomplete outcome data (attrition bias) Rates of loss to follow-up	High risk	“Statistically more subjects assigned to brimonidine (36/99, 36.4%) dropped out prior to the year-1 examination than assigned to timolol (8/79, 10.1%) (P <.001). The most common reason for discontinuation before the year-1 examination was localized ocular allergy that necessitated discontinuing the study medication in 20 of the 99 (20.2%) brimonidine and 3 of the 79 (3.8%) timolol subjects (P < .001).”
Incomplete outcome data (attrition bias) Handling of missing data	High risk	“Collection of data from discontinued patients ceased at their final study visit. Data up to this point were included in the analysis, but discontinued patients were no longer followed as part of the study.”
Selective reporting (reporting bias)	High risk	Definition of primary and secondary outcomes differed between baseline paper and results paper. Results for some outcomes measured were not reported (i.e., cup-disc ratio, visual acuity)
Other bias	High risk	“Publication of this article was supported by an unrestricted grant to the Low-Pressure Glaucoma Study Group from Allergan, Inc, Irvine, California; the Chicago Center for Vision Research, Chicago, Illinois; and an unrestricted grant from Research to Prevent Blindness, Inc, New York, New York (Northwestern University). Study medications were provided by Allergan, Inc. Funding organizations had no role in the design and conduct of the study”

Abbreviations

>: greater than

≥: greater than or equal to

<: less than

≤: less than or equal to

IOP: intraocular pressure

LPG: low-pressure glaucoma