Subthreshold Nanosecond Laser Intervention in Intermediate Age ...

Subthreshold Nanosecond Laser Intervention in Intermediate Age-Related Macular Degeneration Study Design and Baseline Characteristics of the Laser in Early Stages of Age-Related Macular Degeneration Study (Report Number 1) Jia Jia Lek, PhD,1,2 Kate H. Brassington, BOrth(Hons), MPH,1,2 Chi D. Luu, PhD,1,2 Fred K. Chen, MBBS(Hons), PhD,3,4 Jennifer J. Arnold, MBBS(Hons), FRANZCO,5 Wilson J. Heriot, MBBS, FRANZCO,6 Shane R. Durkin, MBBS(Hons), FRANZCO,7 Usha Chakravarthy, MD, PhD,8 Robyn H. Guymer, MBBS, PhD,1,2 for the Laser in Early Stages of Age-Related Macular Degeneration Study Writing Committee* Purpose: The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is an investigation of the safety and efficacy of subthreshold nanosecond laser treatment to slow the progression of intermediate age-related macular degeneration (AMD). This report presents the novel study design and baseline characteristics. Design: Multicenter, double-masked, randomized controlled, medical device feasibility clinical trial. Participants: Persons with bilateral drusen >125 mm within 1500 mm of the fovea, monocular bestcorrected visual acuity (BCVA)
20/40, and microperimetric retinal sensitivity of 63 mm) or large drusen within 2 disc diameters (w3000 mm) from the fovea. To select intermediate AMD cases with a greater risk of progression, our inclusion criteria required at least one >125 mm druse to be within 1500 mm from the fovea in both eyes based on color fundus photography (CFP) (Ferris FL, personal communication, November 20, 2012). In addition, participants were required to have a repeatable relative scotoma (1000 mm) drusenoid pigment epithelial detachment, because our pilot study suggested that these individuals had a higher risk of progression to GA despite treatment.11

Schedule of Assessments Table 3 (available at www.ophthalmologyretina.org) summarizes the schedule of assessments for the LEAD study during the 36-month period. The Qualification visit (visit 1) was conducted up to 8 weeks before the Randomization and Treatment visit (visit 2), when treatment was first initiated. A 1-week posteinitial treatment follow-up telephone call was made to capture any early side effects. Follow-up visits are conducted 1 month from the day of randomization (visit 3, safety visit), with subsequent visits every 6 months (2 weeks) from the day of randomization to 36 months. If a participant remains eligible, re-treatment is initiated within a period of 4 weeks after follow-up visits 4 to 8. The final follow-up visit, visit 9, marks the end of the study. Should new ocular symptoms arise outside of scheduled visits, the participant attends an unscheduled visit to rule out ocular changes including the occurrence of end points.

Study Procedures Candidates for the LEAD study were assessed for eligibility at the qualification visit. Information was collected on participant demographics, personal and family ocular and systemic history including AMD family history, and medications. Participants were categorized as having smoked if they smoked at least 1 cigarette per day, 1 cigar per week, or 30 g of tobacco per month for 1 year. Former smokers were defined as participants who stopped smoking for at least 1 year before enrollment. A positive family AMD risk factor was recorded for participants with parents or siblings with AMD. Changes in systemic health, medications, and supplement intake are updated at follow-up visits 4 to 9. All examination procedures are performed on both eyes, and participants are adjusted to ambient lighting levels (30 cd/m2) for at least 15 minutes before functional assessments, followed by ocular imaging and examination.

Manifest Subjective Refraction and Visual Acuity Measurements The BCVA and subjective refraction are measured using the Early Treatment for Diabetic Retinopathy Study protocol with BCVA recorded as the total number of letters read (0 [20/800] to 100 [20/ 10]). Low luminance visual acuity (LLVA) is measured with a 2.0 log unit neutral density filter (Kodak Wratten filter, Kodak,

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Figure 1. End points (description in Table 2) comprising late age-related macular degeneration (AMD) (A and B) and novel end points for geographic atrophy (GA) (CeH) in the Laser intervention in Early stages of Age-Related Macular Degeneration (LEAD) study. Participants with these end point features were excluded from the LEAD study. A, Choroidal neovascularization (CNV). B, Geographic atrophy. C, Fundus autofluorescence (FAF)defined atrophy, hypofluorescent areas with sharp margins on FAF, corroborated on (D) color fundus photography (CFP) as areas of hypopigmentation but without visible choroidal vessels. E, Spectral-domain optical coherence tomography (SD-OCT)edefined atrophy (indicated by red arrow) on SDOCT with no signs of GA on CFP as shown in (F). G, Nascent geographic atrophy (nGA) (indicated by red arrow) on SD-OCT with no signs of GA on CFP as shown in (H).

Rochester, NY). Low luminance deficit is calculated by subtracting LLVA from BCVA.23

Clinical Eye Examination Ocular examination included slit-lamp biomicroscopy and intraocular pressures. Functional assessment and imaging were performed after pupil dilation of at least 5 mm.

Multifocal Electroretinogram A subset of participants at the CERA site underwent bilateral multifocal electroretinogram (mfERG) testing on the Visual Evoked Response Imaging System (VERIS Science 6; Electrodiagnostic Imaging, Inc, Redwood City, CA) using methods described previously.26

Multimodal Imaging Microperimetry Examination Microperimetry is conducted using the Macular Integrity Assessment (CenterVue, Padova, Italy) microperimeter and a customized grid (AMD 6 grid; CERA, East Melbourne, Australia24) of 37 points located at 0 , 1 , 2.33 , 4 , and 6 from fixation, designed to allow a regular sampling within the macula with a slight increase in density toward the fovea.25 Tests are determined to be reliable if false-positives are 1 Bscan,32 and definite or questionable presence on at least 1 other en face modality (infrared reflectance, FAF, or CFP).31 In the absence of definite SD-OCT RPD, RPDs also were graded as present if RPDs were definitely present on at least 2 en face modalities.31 Presence of RPD was graded as questionable if RPDs were definitely present only on SD-OCT or when RPDs were graded only as questionable on at least 2 en face modalities. Absence of RPD was determined if RPDs were only questionable on 1 modality, only present on 1 en face modality (infrared reflectance, FAF, or CFP), or absent from all modalities. The 2 senior graders and the medical retinal clinician also grade the end points using all multimodal images after the end point has been determined by the EAC.

Night Vision and Vision-Related Quality of Life Questionnaires The 10-item Night Vision Questionnaire (NVQ-10)27 and the 28-item Impact of Vision Impairment (IVI) questionnaire28 are administered at baseline and 12 months.

Blood Draw for DNA Consent was gained for a concurrent study for participants at the CERA and Lions Eye Institute to have blood drawn for DNA storage and subsequent genetic analysis.

Assignment of Study Eye

End-Point Adjudication Committee: Determination of End Points Study end points comprise late AMDeCNV and GA, and anatomic changes on MMI defined as FAF-defined atrophy,22 SD-OCT signs

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Ophthalmology Retina Volume -, Number -, Month 2016 of atrophy,20 and nGA21 (definitions shown in Table 2 and Fig 1). The EAC comprises independent retinal subspecialists who are responsible for the determination of progression to an end point in a participant’s eye. Two senior retinal subspecialists of the EAC review all possible cases thought to have potentially reached an end point. This can occur through the site principal investigator who detects CNV or GA, or the IRC detecting unsuspected optical coherence tomography (OCT) or FAF changes suggestive of impending GA. If consensus is not reached by the EAC, a third member adjudicates the case. The EAC is alerted to the possibility of CNV on the basis of participant’s symptoms, clinical signs, and grading of multimodal images by the IRC. Choroidal neovascularization is then formally determined using fundus fluorescein angiography. When applicable, indocyanine green angiography is used to rule out the presence of polypoidal choroidal vasculopathy. Cases with new onset of subretinal fluid/space on SD-OCT with no leakage on fluorescein angiography or on indocyanine green angiography are diagnosed as nonexudative detachment of the neurosensory retina,33 with no end point determined. The nonexudative detachment of the neurosensory retina cases are reviewed at more frequent unscheduled visits for progression to CNV, and when available, OCT angiography is performed. Formal grading of the type of end points is performed by the IRC after the determination of an end point. Participants who progress to an end point in the study eye are not eligible for re-treatment but remain in the study for observation. If progression to an end point occurs in the nonstudy eye, the study eye continues to receive treatment. When bilateral end points are reached, participants remain in the study for observation without further treatment. Appropriate management is offered to those who develop CNV at the discretion of the site principal investigator. Participants who remain eligible at each 6-month follow-up visit are re-treated. Before treatment, participants are clinically reassessed for any signs of CNV and GA that may have developed between the review and treatment visits.

Outcomes Primary Outcome The primary objective of the LEAD study is the comparison between nanosecond laser (2RT) treatment and sham laser treatment on the time of progression to the study end points: late AMDeCNV or GA, or anatomic end points defined on MMIeFAFedefined atrophy, SD-OCTedefined atrophy or nGA in the study eyes as determined by the EAC and confirmed and defined by the IRC, using MMI, within a 36-month follow-up period. Secondary and Exploratory Outcomes Previously, we have demonstrated in both animals and humans that there appears to be a bilateral beneficial effect from a unilateral nanosecond laser treatment.10,11 Thus, the secondary objective of the LEAD study is to compare the time of progression with end points in the untreated (nonstudy) eye in the treated and sham arms within a 36-month period. Other secondary objectives include comparisons of other clinical indicators of AMD risk of vision loss, such as drusen area or volume and retinal sensitivity at 36 months. Exploratory analysis includes other measures of visual function and quality of life parameters at 36 months.

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Analysis All analyses are performed with SPSS software version 22 (IBM, New York, NY). Results are considered statistically significant if P < 0.05 in this study. Background and Demographic Characteristics, and Baseline Ocular Characteristics The independent t test and chi-square test were used to assess the degree to which comparability of randomization was achieved for continuous and categoric data, respectively, at baseline before treatment. Analyses at 36 Months Data will be analyzed according to intention-to-treat. The primary efficacy outcome, the time to progression to end points in the study eye, will be assessed using a Cox proportional hazards model. Hazard ratios and 95% confidence interval of the nanosecond laser treatment arm will be compared with the sham arm. Cox proportional hazards model will be used to determine whether differences for specific end points exist between treatment arms. Analysis will be performed with potential covariates, including age, pigmentary abnormalities, RPD, and drusen area/volume. Sensitivity analysis will be conducted to explore the bias created by missing data. Similar analysis will be performed to determine an effect in the nonstudy fellow eye. Mixed regression model taking into account repeated measures will be used to investigate whether changes in continuous variables (drusen area [CFP and SD-OCT], drusen volume [SD-OCT], BCVA, low luminance deficit, average and worst-point retinal sensitivities, mfERG implicit time and amplitude, NVQ-10 and IVI scores) are different between treatment arms with covariates over 36 months. Safety Monitoring and Interim Analysis The Data and Safety Monitoring Committee meets every 6 months to review the number of end points and the cases of ocular or systemic events that may be associated with the treatment, and ratify that the study will proceed. As part of the safety monitoring process, an interim analysis of the primary and secondary efficacy variables will be performed when the 150th randomized participant has been followed for 18 months. Treatment arms will remain masked to maintain the integrity of the randomized controlled trial. The interim analysis will provide data regarding the safety of the study and indicate that it is appropriate for the study to be continued. If concerns (HaybittleePeto rule of
3 standard deviations in primary outcome between treatment arms) arise, the Data Safety Monitoring Committee informs the study chair, who makes the final decision about early study termination. No statistical adjustment is made for this single interim analysis because the effect on sample size and P value for the final analysis is considered to be negligible under the HaybittleePeto rule.34

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Sample Size and Power No previous studies have included the inclusion criteria (drusen within 1500 mm of fovea and reduced retinal sensitivity), exclusion criteria (no SD-OCT atrophic changes and drusenoid pigment epithelial detachments), or novel end points (FAF atrophy, SD-OCTedefined preclinical atrophy, and nGA) used in the LEAD study. The Age-Related Eye Disease Study predicted progression rate of 50% over 5 years for patients with bilateral large drusen and pigmentary changes within 3000 mm of fovea.6 We estimate a 50% reduction in this progression rate to study end points in participants receiving nanosecond laser treatment in the LEAD study. By using a Cox proportional hazards model, 126 participants are required per treatment arm to achieve an 80% power to detect a significant (alpha ¼ 0.05, 2-tailed) difference in our primary end point: progression rate to study end points between treatment arms.35 In considering a 10% dropout rate over 3 years and a 2% incomplete block allocation, 141 participants are required per treatment arm.

Results Study Centers and Distribution of Participants for the LEAD Study Enrollment began in July 2012 and ended in April 2015 at 6 clinical sites in Australia and Northern Ireland (Table 4, available at www.ophthalmologyretina.org). A total of 737 patient records were reviewed as potential participants, of whom 367 were considered potentially eligible candidates and underwent screening for eligibility and 292 were deemed eligible and randomized into the clinical trial (Fig 2). Of the 75 individuals found to be ineligible for randomization, the primary reason (64%) was not meeting the inclusion criteria (Fig 2). Of the 292 participants randomized in the study, 2 participants were noted to be receiving glaucoma topical therapy after being randomized. They had normal Humphrey visual fields but were excluded for retinal sensitivity analysis in this study. A total of 145 participants were randomized in arm 1, and 147 participants were randomized in arm 2 (Fig 2), with 1 arm receiving the

Figure 2. Randomization schema of Laser Intervention in Early Stages of Age-Related Macular Degeneration study. *Smokers (current/past smokers) and nonsmokers (never smoked). Treatment arms will be unmasked at the completion of the study.

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Ophthalmology Retina Volume -, Number -, Month 2016 Table 5. LEAD Baseline Participant Background and Demographic Characteristics Arm 1 (n [ 145)

Arm 2 (n [ 147)

P Value

Overall (n [ 292)

70.0, 51e89

70.0, 51e86

P ¼ 0.54

70.0, 51e89

112 (77.2%) 33 (22.8%)

102 (69.4%) 45 (30.6%)

P ¼ 0.13

214 (73.3%) 78 (26.7%)

128 6 4 0 1 5 1

(88.3%) (4.1%) (2.8%) (0%) (0.7%) (3.4%) (0.7%)

134 7 4 1 1 0 0

(91.2%) (4.8%) (2.7%) (0.7%) (0.7%) (0%) (0%)

P ¼ 0.30

262 13 8 1 2 5 1

(89.7%) (4.5%) (2.7%) (0.3%) (0.7%) (1.7%) (0.3%)

4 57 14 9 61

(2.8%) (39.3%) (9.7%) (6.2%) (42.1%)

6 59 19 14 49

(4.1%) (40.1%) (12.9%) (9.5%) (33.3%)

P ¼ 0.47

10 116 33 23 110

(3.4%) (39.7%) (11.3%) (7.9%) (37.7%)

77 62 6 67

(53.1%) (42.8%) (4.1%) (46.2%)

77 66 4 62

(52.4%) (44.9%) (2.7%) (42.2%)

P ¼ 0.77

154 128 10 129

(52.7%) (43.8%) (3.4%) (44.2%)

Characteristic Age (yrs) at randomization (median, range) Gender Female Male Ethnicity Anglo-Saxon Northern European Southern European Asian Indian Other Not sure Education Primary school Secondary school Trade qualification Incomplete university or college training Completed higher degree from university or college Smoking status Never Past Current Hypertension (yes) Intake of supplements Macu-Vision* (Blackmores Limited, Warriewood, NSW, Australia) (yes) Lutein-Visiony (Blackmores Limited) (yes) Macu-Vision or Lutein-Vision (yes) Other supplements (yes) Lens status Study eyes (pseudophakic) Nonstudy eyes (pseudophakic) Family (immediate) history of AMD No Yes Unknown Study (treated) eye (right eye)

P ¼ 0.49

45 (31%)

50 (34%)

P ¼ 0.59

95 (32.5%)

24 (16.6%) 57 (39.3%) 90 (62.1%)

9 (6.1%) 53 (36.1%) 84 (57.1%)

P ¼ 0.005 P ¼ 0.57 P ¼ 0.39

33 (11.3%) 110 (37.7%) 174 (59.6%)

30 (20.7%) 29 (20%)

28 (19%) 27 (18.4%)

P ¼ 0.73 P ¼ 0.72

58 (19.9%) 56 (19.2%)

69 59 17 75

66 61 20 90

P ¼ 0.85

135 (46.2%) 120 (41.1%) 37 (12.7%) 165 (56.5%)

(47.6%) (40.7%) (11.7%) (51.7%)

(44.9%) (41.5%) (13.6%) (61.2%)

P ¼ 0.10

AMD ¼ age-related macular degeneration; LEAD ¼ Laser intervention in Early stages of Age-Related Macular Degeneration. *Active ingredients in Macu-Vision: vitamin C, vitamin E, zinc oxide, and cupric oxide. y Active ingredients in Lutein-Vision: Tagetes erecta (lutein), selenomethionine, zeaxanthin, and concentrated omega-3 triglycerides-fish oil.

nanosecond laser treatment and the other receiving sham treatment. The expected completion date is mid-2018.

Baseline Background and Demographic Characteristics Table 5 shows the baseline background and demographic characteristics of the LEAD cohort. All baseline background and demographic characteristics were well matched between treatment arms with the exception of the supplement intake of Lutein-Vision (Blackmores Limited, Warriewood, NSW, Australia) (P ¼ 0.005). The median age of participants is 70 years, with 73.3% being female and 89.7% being of Anglo-Saxon descent. Thirty-eight percent of the participants have a qualification from a university or college, and 44.2% have hypertension. Only 3.4% of participants are current smokers; however, 43.8% are past smokers. Some 19.9% and 19.2% of participants are pseudophakic in their study and nonstudy eyes, respectively, and 41.1% have a positive family

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history of AMD. The study eye is allocated as the right eye in 56.5% of the participants. A larger percentage of participants take a multivitamin supplement formulated for AMD (Macu-Vision, Blackmores Limited) (32.5%) compared with a macular pigment supplement (Lutein-Vision, Blackmores Limited) (11.3%). Approximately 59% of participants take other vitamins and health supplements.

Baseline Ocular Characteristics (Study and Nonstudy Eyes between Treatment Arms) Baseline characteristics are shown in Tables 6 and 7 for the study and nonstudy eyes. There were no significant differences found with baseline ocular characteristics between treatment arms. The mean BCVA was 83 (20/25) and 86 (20/20) letters for the study and nonstudy eyes, respectively. The LLVA measured using a 2.0 log unit neutral density filter was 68 letters (20/50) and 71 letters (20/40) for study and nonstudy eyes, respectively (n ¼ 291). All participants demonstrated the inclusion criteria of having

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bilateral drusen of >125 mm within 1500 mm from the fovea. The prevalence of pigmentary abnormalities was 33% and 26% in study and nonstudy eyes, respectively. Some 23% and 21% of participants had MMI-defined RPD in their study and nonstudy eyes, respectively. Spectral domain OCT automated drusen area determined using algorithms available in the SD-OCT (Cirrus only available at CERA Site) was 0.770.04 mm (square root, mean  standard error of the mean [SEM]) and 0.690.04 mm in the study and nonstudy eyes, respectively, of 147 participants of the 162 attending the CERA site (15 participants at CERA did not have Cirrus images). Drusen area determined by manual grading of CFP (145 participants attending non-CERA sites, including 15 participants attending the CERA site) was 0.920.03 mm (square root, mean  SEM) and 0.870.03 mm in the study and nonstudy eyes, respectively. A subset of 73 participants at CERA had drusen area measured with SD-OCT (Cirrus) and CFP for study (SD-OCT: 0.790.05, CFP ¼ 0.940.04) and nonstudy (SD-OCT: 0.710.05, CFP ¼ 0.930.04) eyes. Consistent with previous studies, automated SD-OCT measurements were smaller than CFP measurements, and intraclass correlation coefficients were 0.726 (study eyes) and 0.764 (nonstudy eyes), suggesting good agreement between SD-OCT and CFP drusen area measures.36,37 Drusen volume using algorithms available in the SD-OCT (Cirrus, on 147 participants at CERA Site) was 0.260.01 mm (cube root, mean  SEM) and 0.230.01 mm for the study and nonstudy eyes, respectively. Average retinal sensitivities within central 6 were 25.90.1 dB (mean  SEM) and 26.50.1 dB, with worst point retinal sensitivities as 19.90.2 and 21.10.2 in the study and nonstudy eyes, respectively (n ¼ 288, data from 4 participants were excluded with 2 having incorrect test grids and 2 being on glaucoma therapy). Average NVQ-10 (n ¼ 287) and IVI (n ¼ 284) questionnaire scores were 83.41.0 (mean  SEM) and 2.90.01, respectively. In accordance with the protocol, the eye with the worse BCVA or average retinal sensitivity was assigned as the study eye for all participants except for 6 cases. The protocol for determining the study eye was incorrectly followed, such that the eye with better BCVA (5 cases) or retinal sensitivity (1 case) was allocated as the study eye. All except 9 participants had their worse retinal sensitivity points within the central 6 in their study eyes.

Discussion Current treatment to slow down the progression of AMD has been limited to the use of dietary supplements and lifestyle advice.3e5 The safety and efficacy of new interventions preventing the development of late AMD where central vision is threatened remain an active area of research. However, the conduct of intervention trials for early stages of AMD is hampered by the slow progression of AMD, which requires lengthy and costly studies with large sample sizes to see an effect. Recent advances in imaging and functional testing technology present an opportunity to better define participants who are at high risk of progressing to late AMD,38 which we have exploited in the design of the LEAD study with the incorporation of novel eligibility criteria. Current imaging techniques also allowed us to use

early anatomic changes that potentially portend the development of GA as novel end points in the LEAD study. The results of the LEAD study will reveal whether the use of novel eligibility criteria and end points in the study design allowed us to determine the safety and efficacy of nanosecond laser treatment on slowing the progression of intermediate AMD within a feasible time period and in a cost-effective manner, using an achievable sample size. By including the use of FAF-defined atrophy, SDOCTedefined atrophy, and nGA in the LEAD study, we recognize that these features have not been longitudinally followed to determine rates of conversion to GA. More work is needed before we can claim these novel imaging end points as surrogate markers for GA. In our prescreening for the LEAD study, many people with intermediate AMD presented with SD-OCT signs of impending GA, such as disruption or loss of RPE and outer layers of the retina, signs that we have described as nGA.21 Because nGA was commonly observed in those with intermediate AMD as defined by standard criteria (CFP) during our prescreening, we excluded those participants, given that MMI signs suggested that they might already be further along the path toward GA.20,21 Because OCT use was not routinely available in previous population studies of AMD, it is not known to what extent SDOCT atrophic signs were already present in those classified with early or intermediate AMD on the basis of CFP. Excluding people with FAF-defined atrophy, SDOCTedefined atrophy, and nGA from our study meant that it was not possible to easily estimate progression rates on the basis of previous AMD progression studies, such as the AgeRelated Eye Disease Study. The use of only classic definitions of late AMD e CNV and GA as end points in previous studies added to the challenge of defining the study sample sizes required for the LEAD study to detect a difference in progression rate between treatment arms. However, the use of anatomic changes captured on MMI before GA on CFP should result in an increased number and earlier detection of end points, increasing the possibility of detecting a significant difference in progression rate between treatment arms in the LEAD study. This trial, particularly the natural history arm, should enable us to contribute to the understanding of the level of risk these features indicate for progression to GA. In addition, it should allow us to determine whether an intervention that influences the development of late AMD has the same affect on the anatomic end points that we believe occur earlier in the disease progression pathway. To further accelerate and unify clinical research in the earlier stages of AMD, the Classification of Atrophy International Group is currently working to reach a consensus on the nomenclature of OCT changes that portend GA. Through modifications in laser power, wavelength, and pulse duration, several other lasers, used at subthreshold ranges, are being evaluated as a treatment in macular diseases.9,39 The beneficial effects of nanosecond retinal laser treatment have been postulated to involve RPE cell migration and increased production of MMPs, bringing about resolution of extracellular debris within the RPE-BM complex and improved BM conductivity.12,40 The 2RT nanosecond laser, with its short pulse duration at subthreshold energy levels,

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Ophthalmology Retina Volume -, Number -, Month 2016 Table 6. LEAD Participant Baseline Characteristics (Study Eye) Characteristic BCVA (letters) (mean  SEM, range) LLVA (letters) (mean  SEM, range) Low-luminance deficit (letters) (mean  SEM, range) Pigment abnormalities (CFP) Absent Questionable Definitely present Ungradable Hyperpigmentation (CFP) Absent Questionable Definitely present Ungradable Depigmentation (CFP) Absent Questionable Definitely present Ungradable RPD (MMI) Absent Questionable Definitely present Ungradable Drusen area, (square root) mm (SD-OCT) central 3 mm (mean  SEM) Drusen area, (square root) mm (CFP) central 3 mm (participants without SD-OCT measurements) (mean  SEM) Drusen volume, (cube root) mm (SD-OCT) central 3 mm (mean  SEM) Retinal sensitivity Average retinal sensitivity (mean  SEM) Retinal sensitivity (worst point) (mean  SEM) Questionnaires NVQ-10 Questionnaire (mean  SEM) IVI Questionnaire (mean  SEM)

Arm 1 (n [ 145)

Arm 2 (n [ 147)

P Value

Overall (n [ 292)

830.5, 68e95 n ¼ 145 680.8, 15e84 n ¼ 145 150.6, 1e58

830.5, 70e95 n ¼ 146 680.6, 46e87 n ¼ 146 150.4, 0e29

P ¼ 0.97 P ¼ 0.98

830.3, 68e95 n ¼ 291 680.5, 15e87 n ¼ 291 150.4, 0e58

P ¼ 1.00

85 9 51 0

(58.6%) (6.2%) (35.2%) (0%)

93 8 46 0

(63.3%) (5.4%) (31.3%) (0%)

P ¼ 0.72

178 17 97 0

(61%) (5.8%) (33.2%) (0%)

0 10 50 0

(0%) (16.7%) (83.3%) (0%)

1 8 45 0

(1.9%) (14.8%) (83.3%) (0%)

P ¼ 0.56

1 18 95 0

(0.9%) (15.8%) (83.3%) (0%)

52 4 4 0

(86.7%) (6.7%) (6.7%) (0%)

47 3 4 0

(87%) (5.6%) (7.4%) (0%)

P ¼ 0.96

99 7 8 0

(86.8%) (6.1%) (7%) (0%)

P ¼ 0.84

108 (74.5%) 2 (1.4%) 35 (24.1%) 0 (0%) n ¼ 73 0.790.05 n ¼ 72 0.920.04

111 (75.5%) 1 (0.7%) 35 (23.8%) 0 (0%) n ¼ 74 0.760.05 n ¼ 73 0.920.04

n ¼ 73 0.270.02

n ¼ 74 0.260.02

P ¼ 0.75

n ¼ 147 0.260.01

n ¼ 144 26.00.1 n ¼ 144 20.20.3

n ¼ 144 25.80.2 n ¼ 144 19.60.3

P ¼ 0.35

n ¼ 288 25.90.1 n ¼ 288 19.90.2

n ¼ 142 83.51.5 n ¼ 140 2.870.02

n ¼ 145 83.21.4 n ¼ 144 2.880.02

P ¼ 0.66 P ¼ 1.00

P ¼ 0.14 P ¼ 0.89 P ¼ 0.50

219 (75%) 3 (1%) 70 (24%) 0 (0%) n ¼ 147 0.770.04 n ¼ 145 0.920.03

n ¼ 287 83.41.0 n ¼ 284 2.880.01

BCVA ¼ best-corrected visual acuity; CFP ¼ color fundus photography; IVI ¼ Impact of Vision Impairment; LEAD ¼ Laser intervention in Early stages of Age-Related Macular Degeneration; LLVA ¼ low-luminance visual acuity; MMI ¼ multimodal imaging; NVQ-10 ¼ 10-item Night Vision Questionnaire; RPD ¼ reticular pseudodrusen; SD-OCT ¼ spectral-domain optical coherence tomography; SEM ¼ standard error of the mean.

confines heat within the RPE cells to result in selective RPE cell death with no detectable effect on the overlying or surrounding neurosensory retina.10,41,42 This is unlike the collateral retinal damage that occurs with thermal laser treatment. Also, instead of the top-hat beam of thermal lasers, the 2RT uses a speckled beam that results in a nonconfluent area of RPE damage within the irradiated zone.42 It is postulated that the residual unaffected RPE cells slide or possibly divide to cover the defect.42 The selective targeting of RPE cells and the ensuing healing response are potentially desirable therapeutic features in interventions for AMD, as well as for other macular diseases, including diabetic macular edema.43 In addition to investigating whether nanosecond laser treatment reduces the number of end point cases compared

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with the sham treatment, the LEAD study will reveal whether the intervention alters clinical indicators of AMD. We will determine whether nanosecond laser intervention will reduce drusen load (area and volume) and improve visual function as indicated by retinal sensitivity, mfERG, LLVA, and questionnaire outcomes. The results of the LEAD study will be representative of the effect of nanosecond laser treatment on a high-risk subset of participants with intermediate AMD defined by MMI and functional testing. The expansion of the clinical group of AMD for which the treatment may be applicable will require further study. However, the results will be important in the current environment where early adopters are already using subthreshold lasers as an intervention in the early stages of AMD, despite the current lack of randomized controlled

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Table 7. LEAD Participant Baseline Characteristics (Nonstudy Eye) Characteristic BCVA (letters) (mean  SEM, range) LLVA (letters) (mean  SEM, range) Low luminance deficit (letters) (mean  SEM, range) Pigment abnormalities (CFP) Absent Questionable Definitely present Ungradable Hyperpigmentation (CFP) Absent Questionable Definitely present Ungradable Depigmentation (CFP) Absent Questionable Definitely present Ungradable Reticular pseudodrusen (MMI) Absent Questionable Definitely present Ungradable Drusen area, (square root) mm (SD-OCT) central 3 mm (mean  SEM) Drusen area, (square root) mm (CFP) central 3 mm (participants without SD-OCT measurements) (mean  SEM) Drusen volume, (cube root) mm (SD-OCT) central 3 mm (mean  SEM) Retinal Sensitivity Average retinal sensitivity (mean  SEM) Retinal sensitivity (worst point) (mean  SEM)

Arm 1 (n [ 145)

Arm 2 (n [ 147)

P Value

Overall (n [ 292)

860.5, 72e99 n ¼ 145 720.7, 15e87 n ¼ 145 150.6, 4e69

860.4, 70e96 n ¼ 146 720.6, 46e86 n ¼ 146 140.5, 3e43

P ¼ 0.92 P ¼ 0.61

860.3, 70e99 n ¼ 291 720.5, 15e87 n ¼ 291 150.4, 3e69

P ¼ 0.44

101 7 39 0

(68.7%) (4.8%) (26.5%) (0%)

P ¼ 0.36

196 20 76 0

(67.1%) (6.8%) (26%) (0%)

(2%) (24%) (74%) (0%)

0 8 38 0

(0%) (17.4%) (82.6%) (0%)

P ¼ 0.44

1 20 75 0

(1%) (20.8%) (78.1%) (0%)

(92%) (2%) (6%) (0%)

40 3 3 0

(87%) (6.5%) (6.5%) (0%)

P ¼ 0.53

86 4 6 0

(89.6%) (4.2%) (6.3%) (0%)

95 13 37 0

(65.5%) (9%) (25.5%) (0%)

1 12 37 0 46 1 3 0

P ¼ 0.15

114 (78.6%) 1 (0.7%) 30 (20.7%) 0 (0%) n ¼ 73 0.670.05 n ¼ 72 0.880.04

105 (71.4%) 5 (3.4%) 37 (25.2%) 0 (0%) n ¼ 74 0.710.05 n ¼ 73 0.850.04

n ¼ 73 0.220.02

n ¼ 74 0.250.02

P ¼ 0.18

n ¼ 147 0.230.01

n ¼ 144 26.60.2 n ¼ 144 21.20.3

n ¼ 144 26.40.2 n ¼ 144 20.90.3

P ¼ 0.53

n ¼ 288 26.50.1 n ¼ 288 21.10.2

P ¼ 0.57 P ¼ 0.58

P ¼ 0.44

219 (75%) 6 (2.1%) 67 (22.9%) 0 (0%) n ¼ 147 0.690.04 n ¼ 145 0.870.03

BCVA ¼ best-corrected visual acuity; CFP ¼ color fundus photography; LEAD ¼ Laser intervention in Early stages of Age-Related Macular Degeneration; LLVA ¼ low luminance visual acuity; MMI ¼ multimodal imaging; SD-OCT ¼ spectral-domain optical coherence tomography; SEM ¼ standard error of the mean.

trial data. Risk characteristics for progression to study end points are equally distributed between treatment arms at baseline, except for Lutein-Vision supplement intake. The LEAD study is well placed to address its main aims, and the results of the study will be reported in 2018. Acknowledgments. Acknowledgments are listed in Appendix 2 (available at www.ophthalmologyretina.org).

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Lek et al



LEAD Study Design and Baseline Characteristics

Footnotes and Financial Disclosures Originally received: September 19, 2016. Final revision: November 30, 2016. Accepted: December 1, 2016. Available online: ---. Manuscript no. ORET_2016_97. 1

Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Victoria, Australia.

2

Ophthalmology, University of Melbourne, Department of Surgery, Victoria, Australia.

3

Centre for Ophthalmology and Visual Science (incorporating Lions Eye Institute), The University of Western Australia, Perth, Western Australia, Australia.

4

Department of Ophthalmology, Royal Perth Hospital, Perth, Western Australia, Australia.

L.L.L.: Grant d AbbVie, Bayer; advisory board, consultant d AbbVie, Bayer, Allergen. J.R.: Consultant (outside of submitted work) d Ellex R & D Pty Ltd. U.C.: Grant d Bayer, Novartis, Roche; advisory board and speaker fees d Bayer, Novartis, Roche. J.J.A.: Advisory board and personal fees d Bayer, Novartis. R.H.G.: Advisory board d Bayer, Novartis. R.P.F.: Consultant d Bayer, Santeen, Opthea, QLT Inc; consultant and grant d Novartis. S.S.: Grant d Allergan, Bayer; advisory board d Novartis Author Contributions:

5

Marsden Eye Research, Sydney, Australia.

6

Heriot Eyecare, Victoria, Australia. Adelaide Eye and Retinal Centre, Adelaide, Australia.

Research design: Guymer, Brassington, Luu, Keller Data acquisition and/or research execution: Guymer, Chen, Arnold, Heriot, Durkin, Chakravarthy, Brassington, Aung, Baglin, Caruso, Cohn, Fagan, Finger, Harper, Hodgson, Lim, Makeyeva, Qatarneh, Robman, Runciman, Sandhu, Sharangan, Wijngaarden, Wickremasinghe

Belfast Health and Social Care Trust, Belfast, Northern Ireland.

Data analysis and/or interpretation: Guymer, Lek, Luu, Hodgson, Tindill

7 8

*Laser in Early Stages of Age-Related Macular Degeneration Study Writing Committee is listed in Appendix 1 (available at www. ophthalmologyretina.org). Supported by the National Health & Medical Research Council of Australia (Project Grant APP1027624 [CDL and RHG] and fellowship [RHG]: GNT1103013 [FKC]: APP1054712), and BUPA Health Foundation (Australia) (CDL and RHG). CERA receives operational infrastructure support from the Victorian Government. Ellex R&D Pty Ltd (Adelaide, Australia) provides partial funding to the coordinating center for the trial and provides lasers, and services both lasers and microperimeters for the duration of the study. The funding organizations had no role in the design or conduct of this research. Financial Disclosure(s): The author(s) have made the following disclosure(s): C.A.H.: Advisory board d Novartis, Bayer; Director of Adverum Australia Biotechnologies. F.K.C.: grant d Bayer AG, Novartis; Grant and personal fees d Allergan; personal fees d Heidelberg Engineering; advisory board d Alcon; consultant d Pfizer.

Abbreviations and Acronyms: AMD ¼ age-related macular degeneration; BCVA ¼ best-corrected visual acuity; BM ¼ Bruch’s membrane; CERA ¼ Centre for Eye Research Australia; CFP ¼ color fundus photography; CNV ¼ choroidal neovascularization; dB ¼ decibels; EAC ¼ End-Point Adjudication Committee; FAF ¼ fundus autofluorescence; GA ¼ geographic atrophy; IRC ¼ Image Reading Center; IVI ¼ Impact of Vision Impairment; LEAD ¼ Laser intervention in Early stages of Age-Related Macular Degeneration; LLVA ¼ low-luminance visual acuity; mfERG ¼ multifocal electroretinogram; MMI ¼ multimodal imaging; MMP ¼ metalloproteinase; nGA ¼ nascent geographic atrophy; NVQ-10 ¼ 10-item Night Vision Questionnaire; OCT ¼ optical coherence tomography; RPD ¼ reticular pseudodrusen; RPE ¼ retinal pigment epithelium; SD-OCT ¼ spectraldomain optical coherence tomography; SEM ¼ standard error of the mean. Correspondence: Robyn H. Guymer, MBBS, PhD, Centre for Eye Research Australia, Locked Bag 8, East Melbourne, Victoria 8002, Australia. E-mail: rhg@ unimelb.edu.au.

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