Abstract
PURPOSE:
To assess the relationship between best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) features in noninfectious uveitis (NIU)-related macular edema.
DESIGN:
Clinical cohort study from post hoc analysis of 2 phase 3 clinical trials.
METHODS:
Correlation and longitudinal treatment analyses were performed. Of 198 patients with NIU, 134 received suprachoroidal CLS-TA (proprietary formulation of a triamcinolone acetonide injectable suspension), and 64 received sham, with 12.9% and 72%, respectively, receiving rescue therapy.
RESULTS:
At baseline, mean BCVA progressively worsened with each ordinal drop in central subfield ellipsoid zone (EZ) integrity. Eyes with normal baseline EZ experienced greater 24-week change in BCVA versus those with some degree of baseline EZ disruption (11.9 vs 9.4 letters, P = .006). In contrast, eyes with baseline central subfield cystoid spaces and/or subretinal fluid showed more improvement (13.7 or 17.2 letters, respectively) at 24 weeks, versus those without such findings (5.5 [P = .012] or 9.5 letters [P < .001], respectively). Longitudinal modeling for CLS-TA–treated eyes showed that central subfield thickness (CST) reached 90% of maximal improvement by week 3, whereas 90% maximal response in BCVA was not reached until week 9. CLS-TA-treated eyes that showed CST reduction of ≥50 μm at 4 weeks experienced a greater 24-week improvement in BCVA versus those without such an early response (14.6 vs 6.5 letters, P = .006 for difference).
CONCLUSIONS:
Pretreatment EZ integrity and the presence of central subfield cystoid spaces or subretinal fluid each predict improved therapeutic response to treatment in eyes with NIU. In CLS-TA treated eyes, longitudinal modeling shows CST improvement preceding BCVA improvement.
Although there is limited correlation between best-corrected visual acuity (BCVA) and central subfield thickness (CST) on optical coherence tomography (OCT),1–8 CST represents an important secondary anatomic end point and a component of retreatment criteria in clinical trials for macular edema (ME). Furthermore, in clinical practice, physicians often base treatment decisions on both BCVA and OCT assessments. Although several large studies have examined the relationship between BCVA and CST in patients with diabetic ME (DME)1–4 and ME due to retinal vein occlusion (RVO),3–7 there is limited literature on OCT anatomic and temporal biomarkers in ME due to noninfectious uveitis (NIU),4,8,9 the most common cause of vision loss in NIU.10 In a post hoc analysis of clinical trial data involving patients with NIU-ME, a recent study noted moderate correlation between BCVA and CST, both at baseline and for change from baseline to 24 weeks after treatment with an intraocular corticosteroid or sham.4
The current study assessed the relationship between BCVA and OCT anatomic and temporal features in NIU-ME based on data sets from 2 Phase 3 clinical trials, with monitor-verified diagnoses per eligibility criteria, protocol refractions, study-certified imagers, and spectral domain OCT evaluation at a centralized masked reading center. These clinical trials (PEACHTREE and AZALEA) assessed CLS-TA (Clearside Biomedical), a proprietary formulation of the corticosteroid triamcinolone acetonide for suprachoroidal (SC) injection, which was recently approved by the United States Food and Drug Administration for the treatment of ME associated with uveitis.11,12
This report, however, primarily focuses on structure-function correlations and novel modeling of treatment response. Specifically, relationships were assessed between BCVA and the presence or absence of central subfield cystoid spaces, subretinal fluid (SRF), and integrity of the ellipsoid zone (EZ), also known as the photoreceptor inner segment/outer segment (IS/OS) junction.
Correlation analyses were performed to describe the relationships between BCVA and OCT anatomic features at baseline, between change from baseline in BCVA and baseline OCT anatomic features, and between the change from baseline over time in both BCVA and OCT anatomic features. In addition, a longitudinal treatment response analysis modeled the temporal relationship between change in BCVA and CST, whereas an early CST anatomic response was assessed for week 24 BCVA outcome in CLS-TA–treated patients with ME.
METHODS
CLINICAL TRIALS:
This post hoc analysis was performed on data sets from 2 Phase 3 studies (1 randomized controlled clinical trial and 1 open-label uncontrolled trial) assessing CLS-TA, 4 mg (0.1 mL of 40 mg/mL) administered SC as monotherapy in patients diagnosed with NIU, most of whom showed ME at baseline. This post hoc study involved analysis of already collected deidentified information from clinical trial protocols that were approved by an Institutional Review Board (IRB) or independent ethics committee at each study site, and these previously conducted studies were performed in compliance with the provisions of the Declaration of Helsinki, International Conference on Harmonization Good Clinical Practice guidelines, and the applicable local regulations. Written informed consent was obtained from each patient before enrollment into the study using IRB-approved informed consent forms.
Patients with NIU, with or without ME, were assessed every 4 weeks for 24 weeks. Both studies included verified diagnoses, BCVA measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, and masked reading center assessment of OCT images. The study designs are summarized below, and key eligibility are summarized in Table 1.
TABLE 1.
Studies Included in the Analysis.
| Feature | Study |
|
|---|---|---|
| PEACHTREE | AZALEA | |
| ClinicalTrials.gov identifier | NCT02595398 | NCT03097315 |
| Study title | PEACHTREE: A Phase 3, randomized, masked, controlled clinical trial to study the safety and efficacy of triamcinolone acetonide injectable suspension (CLS-TA) for the treatment of patients with macular edema associated with NIU | AZALEA: Open-label safety study of suprachoroidal triamcinolone acetonide injectable suspension in patients with NIU |
| Disease state | NIU | NIU |
| Phase | 3 | 3 |
| Duration | 24 weeks | 24 weeks |
| Study design | Randomized, double-masked, multicenter | Open-label, multicenter |
| Treatment(s)a | CLS-TA 4 mg at weeks 0 and 12 or sham suprachoroidal injection | CLS-TA 4 mg at weeks 0 and 12 |
| Key eligibility features | Diagnosis of ME associated with NIU; ETDRS BCVA between 5 and 70 letters; CST ≥300 μm | Diagnosis of NIU; ETDRS BCVA ≥ 5 letters |
| Number of Patients | 96 CLS-TA 4 mg; 64 sham suprachoroidal injection | 38 CLS-TA 4 mg |
BCVA = best-corrected visual acuity; CST = central subfield retinal thickness; ETDRS = Early Treatment Diabetic Retinopathy Study; ME = macular edema; NIU = noninfectious uveitis.
Patients were eligible for rescue at other visits as determined by predefined criteria.
PEACHTREE (Suprachoroidal Injection of CLS-TA in Subjects With Macular Edema Associated With Non-infectious Uveitis) (NCT02595398) was a Phase 3, randomized, masked, sham-controlled, multicenter clinical study, conducted in the United States, India, and Israel, in patients diagnosed with ME associated with NIU, including baseline CST of ≥300 μm, and BCVA between 5 and 70 letters, inclusively, in the study eye. The study details are further summarized in Table 1 and in Yeh et al.11
AZALEA (Suprachoroidal Injection of CLS-TA in Patients With Non-infectious Uveitis) (NCT03097315) was a Phase 3, open-label, multicenter safety study conducted in the United States, in patients with NIU, with or without ME and BCVA ≥5 letters in the study eye. The study details are further summarized in Table 1 and in Henry et al.12
In PEACHTREE, patients received 2 unilateral CLS-TA injections or sham SC injections administered 12 weeks apart. In AZALEA, all patients received 2 unilateral CLS-TA injections administered 12 weeks apart. Patients were monitored every 4 weeks for 24 weeks. Beginning at week 4, patients meeting protocol-specified rescue criteria could receive additional therapy implemented at the discretion of the investigator.
SPECTRAL DOMAIN OCT:
Central subfield thickness, presence and location of cystoid spaces and subretinal fluid, as well as EZ integrity in the central subfield were assessed via OCT. The central subfield is a circular area of 1-mm diameter around the center point. For each scan, the standard 9-field ETDRS grid was centered at the fovea, by viewing all B-scans to locate foveal landmarks, which included the point at which the inner retinal layers were thinnest, and the foveal depression and/or hyperreflective dot that corresponded to reflected light at the foveal center.13 These landmarks are helpful to locate the center point, particularly in the presence of ME. No instrument-specific upper limit for CST was used for study enrollment because eligibility criteria across the clinical trials did not include an upper bound.
The central subfield EZ, SRF, and cystoid spaces were all graded by a masked reading center. The integrity of the EZ in the central subfield was graded as normal, questionably abnormal, definitely abnormal (patchy), definitely abnormal (absent), and cannot grade. Cystoid spaces and subretinal fluid were graded as absent, questionable, definite presence outside central subfield, or definite presence with central subfield involved. Insufficient image quality was indicated as cannot grade.
The OCT instrument and technician were certified before any participants were screened. Research sites were encouraged to use the same technician and equipment throughout the patient’s study participation. Deidentified images were uploaded to a central reading center for masked analysis and interpretation.
BCVA ASSESSMENT:
BCVA was evaluated by ETDRS using electronic visual acuity or standardized lighting and lanes. The results were reported as the total number of letters read following protocol refraction. Visual acuity testing preceded any examination requiring contact with the eye. To provide standardization and well-controlled assessments of BCVA during the study, all BCVA assessments were performed by trained staff who were certified on the study procedure using certified visual acuity equipment/lanes.
CORRELATION ANALYSES:
Post hoc analysis was performed with data from 2 clinical trials (PEACHTREE, AZALEA). All participants in these studies received SC CLS-TA or a sham SC injection. Because the primary purpose of this analysis was to assess correlations between BCVA and OCT anatomic features, and not to assess treatment efficacy, data from all patients were included, regardless of treatment assignment or the administration of rescue therapy.
Pooled data from both studies were analyzed. Analyses of correlation were performed on data collected before dose administration at baseline and separately on the change from baseline data collected after treatment through week 24. Only participants with complete data (i.e., BCVA and OCT assessed on the same date) were included in the analysis. As noted previously, central subfield OCT findings, including the presence and location of cystoid spaces, presence or absence of SRF, and EZ integrity were each graded into 4 levels of severity, in addition to cannot grade. Values of cannot grade were excluded from these analyses, and values for missing data were not imputed. Using the pooled data, a 1-way analysis of covariance with baseline anatomy as the independent variable and baseline CST and age as the covariates and Tukey-Kramer adjustment for multiple comparisons was performed to compare mean BCVA across the anatomic grades at baseline. To assess the fitness of this model, via comparison of the R2 values, analysis of variance was used with baseline anatomy as the independent variable.
To assess the relationship between baseline central subfield OCT findings, including EZ, cystoid spaces, and SRF on 24-week change in BCVA, an analysis of covariance model was used with change from baseline in BCVA as the dependent variable and baseline central subfield anatomy (normal vs not normal with respect to EZ, and not central subfield involved vs central subfield involved for cystoid spaces and SRF) as the independent variable, with age, baseline BCVA, and baseline CST as the covariates. The relationship between the change from baseline in BCVA and the change in the anatomic status at week 24 was assessed using an analysis of covariance model with status of central subfield OCT findings, including EZ, cystoid spaces, or SRF, categorized as any improvement (≥1 level) vs no improvement or worsening, as the independent variable, and age, baseline BCVA, and baseline CST as covariates. To assess the fitness of this model, analysis of variance was used with change in anatomy as the independent variable.
Temporal structure function correlations were determined by assessing the predictive ability of an early anatomic response on longer-term change in vision in eyes receiving SC-administered CLS-TA and a baseline CST of 300 μm or more. Mean change from baseline in BCVA at week 24 was compared between those eyes showing a reduction in CST of 50 μm or more at week 4 (defined as a responder) vs those with less improvement (defined as a limited responder). An analysis of variance model was used with week 4 CST response status (responder vs limited responder), country of enrollment, and their interaction as fixed effects.
Mean and standard error of the mean (SE) values of BCVA presented in the results and tables reflect the simple arithmetic averages, that is, the sample mean and sample SE, calculated within each group, whereas the between-group differences and 95% CIs are based on the least square means derived from the analysis of covariance models, which adjust the group means for other factors included in the model (e.g., baseline CST and age). Reported P values were not adjusted for multiple testing due to the post hoc exploratory nature, and consequently, reported P values are generally viewed as nominal and typically used in hypothesis-generation for future study. All tests were evaluated with a 2-sided α-level of 0.050. Statistical analysis was conducted using SAS 9.4 software (SAS Institute, Inc).
LONGITUDINAL RESPONSE MODEL:
The objective of this longitudinal analysis was to develop a response model that accurately characterized the temporal changes in BCVA and CST after SC administration of CLS-TA and was performed with data from the PEACHTREE and AZALEA clinical trials. The population response analysis included those patients who had at least 1 measurement of BCVA and CST after initiation of treatment. The analysis was conducted according to the United States Food and Drug Administration guidance for Industry on Population Pharmacokinetics and Exposure-Response, and the European Union guidance on Reporting the Results of Population Pharmacokinetic Analyses. The model-based response analysis included factors for disease progression effects, drug effects after administration of CLS-TA, and rescue therapy effects. The typical profiles for both BCVA and CST response after CLS-TA therapy were developed.
Reported P values were not adjusted for multiple testing due to the post hoc exploratory nature of this longitudinal analysis, and as noted above, reported P values should be viewed as nominal in hypothesis generation for future study. All tests were evaluated with a 2-sided α-level of 0.050. Statistical analysis was conducted using R 3 or higher software (R Foundation for Statistical Computing) or SAS 9.4 or higher. A detailed description of the analysis methods and outcome results of the model building process, including tables and figures for BCVA and CST, are available in the Supplemental Material.
RESULTS
A total of 198 eyes from 198 patients contributed BCVA and OCT anatomy data to this analysis, with all eyes being diagnosed with NIU, 172 (87%) of which showed ME (CST >300 μm) at baseline. Demographic, baseline, and disease characteristics and signs of inflammation were well-balanced between the 2 studies, with a few exceptions resulting from differences in study design. Racial distribution disparities existed with PEACHTREE, which was conducted internationally, enrolling an equal proportion of White (65/160, 41%) and Asian (India) (72/160, 45%) patients, and AZALEA, conducted in the United States, enrolling mostly White patients (31/38, 82%). Mean BCVA at baseline in PEACHTREE, which required ME at baseline, was worse than in AZALEA, which did not require ME at baseline, (54.2 letters vs 68.9 letters, respectively) and mean CST was correspondingly greater (498.7 μm vs 335.9 μm, respectively). Demographic and baseline characteristics data are summarized in Table 2, and baseline signs of inflammation and disease characteristics are summarized in Table 3. Of 198 patient eyes, 134 received SC CLS-TA and 64 received sham control. Seventeen (12.9%) in the CLS-TA group received rescue treatment compared with 46 (72%) in the sham control. As described in the following sections, associations between BCVA and OCT anatomy are summarized in Table 4 (Baseline), Table 5 (24-week changes in BCVA and baseline OCT), and Table 6 (24-week changes in BCVA and 24-week changes in OCT).
TABLE 2.
Demographics and Baseline Characteristics.
| Characteristic | Study |
Total | |
|---|---|---|---|
| PEACHTREE | AZALEA | ||
| (n = 160) | (n = 38) | (N = 198) | |
| Age, y | |||
| Mean (SE) | 50.2 (1.15) | 52.4 (2.56) | 50.6 (1.05) |
| Median | 51.0 | 50.5 | 51.0 |
| Minimum, maximum | 18, 92 | 22, 77 | 18, 92 |
| Sex | |||
| Male | 72 (45.0) | 13 (34.2) | 85 (42.9) |
| Female | 88 (55.0) | 25 (65.8) | 113 (57.1) |
| Race | |||
| White | 65 (40.6) | 31 (81.6) | 96 (48.5) |
| Black/African American | 22 (13.8) | 7 (18.4) | 29 (14.6) |
| Asian | 72 (45.0) | 0 | 72 (36.4) |
| Other | 1 (0.6) | 0 | 1 (0.5) |
| Lens status | |||
| Pseudophakic | 71 (44.4) | 14 (36.8) | 85 (42.9) |
| Phakic | 89 (55.6) | 24 (63.2) | 113 (57.1) |
| Baseline BCVA, letters | |||
| Mean (SE) | 54.2 (1.07) | 68.9 (3.09) | 57.0 (1.12) |
| Median | 56.0 | 75.5 | 58.5 |
| Minimum, maximum | 9, 89 | 21, 90 | 9, 90 |
| Baseline CST, μm | |||
| Mean (SE) | 498.7 (12.35) | 335.9 (13.79) | 467.5 (11.28) |
| Median | 481.5 | 317.0 | 440.0 |
| Minimum, maximum | 256, 971 | 176, 559 | 176, 971 |
ZALEA = Open-label Safety Study of Suprachoroidal Triamcinolone Acetonide Injectable Suspension in Patients with Non-Infectious Uveitis; BCVA = best-corrected visual acuity; CST = central subfield retinal thickness; PEACHTREE = A Phase 3, Randomized, Masked, Controlled Clinical Trial to Study the Safety and Efficacy of Triamcinolone Acetonide Injectable Suspension (CLS-TA) for the Treatment of Patients with Macular Edema associated with Non-Infectious Uveitis; SE = standard error of the mean.
Note: Data are shown as n (%) unless indicated otherwise.
TABLE 3.
Baseline Signs of Inflammation and Disease Characteristics.
| Characteristic | Study |
Total | |
|---|---|---|---|
| PEACHTREE | AZALEA | ||
| Time since diagnosed, wk | (n = 160) | (n = 38) | (N = 198) |
| Mean (SE) | 37.3 (4.03) | 35.0 (7.79) | 36.9 (3.58) |
| Median | 16.4 | 15.2 | 15.8 |
| Minimum, maximum | 0, 316 | 0, 242 | 0, 316 |
| Presence of | |||
| Anterior uveitis | 41 (25.6) | 12 (31.6) | 53 (26.8) |
| Intermediate uveitis | 57 (35.6) | 15 (39.5) | 72 (36.4) |
| Posterior uveitis | 35 (21.9) | 10 (26.3) | 45 (22.7) |
| Panuveitis | 52 (32.5) | 10 (26.3) | 62 (31.3) |
| Onset type | |||
| Sudden | 35 (21.9) | 16 (42.1) | 51 (25.8) |
| Insidious | 125 (78.1) | 20 (52.6) | 145 (73.2) |
| Unknown | 0 | 2 (5.3) | 2 (1.0) |
| Duration | |||
| Limited, ≤3 months | 27 (16.9) | 5 (13.2) | 32 (16.2) |
| Persistent, >3 months | 133 (83.1) | 31 (81.6) | 164 (82.8) |
| Unknown | 0 | 2 (5.3) | 2 (1.0) |
| Course | |||
| Acute | 11 (6.9) | 1 (2.6) | 12 (6.1) |
| Recurrent | 48 (30.0) | 11 (28.9) | 59 (29.8) |
| Chronic | 101 (63.1) | 24 (63.2) | 125 (63.1) |
| Unknown | 0 | 2 (5.3) | 2 (1.0) |
| Anterior chamber cells | |||
| 0 | 87 (54.4) | 17 (44.7) | 104 (52.5) |
| 0.5+ | 34 (21.3) | 13 (34.2) | 47 (23.7) |
| 1+ | 22 (13.8) | 6 (15.8) | 28 (14.1) |
| 2+ | 11 (6.9) | 2 (5.3) | 13 (6.6) |
| 3+ | 6 (3.8) | 0 | 6 (3.0) |
| 4+ | 0 | 0 | 0 |
| Anterior chamber flare | |||
| 0 | 105 (65.6) | 27 (71.1) | 132 (66.7) |
| 0.5+ | 0 | 1 (2.6) | 1 (0.5) |
| 1+ | 40 (25.0) | 4 (10.5) | 44 (22.2) |
| 2+ | 15 (9.4) | 2 (5.3) | 17 (8.6) |
| 3+ | 0 | 4 (10.5) | 4 (2.0) |
| 4+ | 0 | 0 | 0 |
| Vitreous haze | |||
| 0 | 40 (25.0) | 17 (44.7) | 57 (28.8) |
| 0.5+ | 36 (22.5) | 5 (13.2) | 41 (20.7) |
| 1+ | 51 (31.9) | 9 (23.7) | 60 (30.3) |
| 1.5+ | 3 (1.9) | 1 (2.6) | 4 (2.0) |
| 2+ | 28 (17.5) | 4 (10.5) | 32 (16.2) |
| 3+ | 2 (1.3) | 1 (2.6) | 3 (1.5) |
| 4+ | 0 | 1 (2.6) | 1 (0.5) |
AZALEA = Open-label Safety Study of Suprachoroidal Triamcinolone Acetonide Injectable Suspension in Patients with Non-Infectious Uveitis; PEACHTREE = A Phase 3, Randomized, Masked, Controlled Clinical Trial to Study the Safety and Efficacy of Triamcinolone Acetonide Injectable Suspension (CLS-TA) for the Treatment of Patients with Macular Edema associated with Non-Infectious Uveitis; SE = standard error of the mean.
Note: Data are shown as n (%) unless indicated otherwise.
TABLE 4.
Association Between Best-Corrected Visual Acuity and Ellipsoid Zone Integrity.
| Baseline BCVA, letters | Baseline Ellipsoid Zone Status |
|||
|---|---|---|---|---|
| Normal (1) | Questionably Abnormal (2) | Definitely Abnormal (Patchy) (3) | Definitely Abnormal (Absent) (4) | |
| (n = 59) | (n = 40) | (n = 29) | (n = 16) | |
| Mean (SE)a | 64.6 (2.11) | 59.1 (2.23) | 52.4 (2.60) | 38.4 (3.58) |
| Difference (95% CI) vs 1b | — | 3.2 (−4.8, 11.2) | 7.5 (−1.8, 16.9) | 20.1 (8.2. 32.0) |
| P value vs 1 | — | .721 | 0.159 | <.001 |
| Difference (95% CI) vs 2 | — | — | 4.3 (−5.1, 13.7) | 16.9 (5.2, 28.6) |
| P value vs 2 | — | — | .633 | .001 |
| Difference (95% CI) vs 3 | — | — | — | 12.6 (0.7, 24.5) |
| P value vs 3 | — | — | — | .034 |
| Baseline Ellipsoid Zone |
||||
| Change from Baseline in BCVA at Week 24 | Normal | Not Normal | ||
|
| ||||
| (n = 53) | (n = 83) | |||
| Mean (SE)a | 11.9 (1.95) | 9.4 (1.46) | ||
| Difference (95% CI)c | — | 6.6 (1.9, 11.3) | ||
| P value | — | .006 | ||
| Change From Baseline in Ellipsoid Zone at Week 24 |
||||
| Change from Baseline in BCVA at Week 24 | Any Improvement | No Improvement or Worsening | ||
|
| ||||
| (n = 55) | (n = 78) | |||
| Mean (SE) a | 12.3 (1.87) | 9.4 (1.53) | ||
| Difference (95% CI)d | — | 1.4 (−2.9, 5.8) | ||
| P value | — | .512 | ||
BCVA = best-corrected visual acuity; CI = confidence interval; CST = central subfield retinal thickness; SE = standard error of the mean.
Note: Spectral-domain optical coherence tomography images with reading center grades of “cannot grade” are excluded from the analysis.
Values represent the sample mean and sample standard error within each group.
Between-group differences and 95% CIs are based on the least square means derived from an analysis of covariance model with baseline BCVA as the dependent variable and the baseline ellipsoid zone grade as the independent variable and baseline CST and age as covariates. P values are adjusted using the Tukey-Kramer method for multiple comparisons.
Between-group differences and 95% CIs are based on the least square means derived from an analysis of covariance model with change from baseline in BCVA at week 24 as the dependent variable, the baseline ellipsoid zone grade as the independent variable, and baseline BCVA, baseline CST, and age as covariates.
Between-group differences and 95% CIs are based on the least square means derived from an analysis of covariance model with change from baseline in BCVA at week 24 as the dependent variable, the change from baseline in ellipsoid zone as the independent variable, and baseline BCVA, baseline CST, and age as covariates.
TABLE 5.
Association Between Best-Corrected Visual Acuity and Presence and Location of Cystoid Spaces.
| Baseline BCVA, letters | Baseline Presence of Cystoid Spaces |
|||
|---|---|---|---|---|
| Absent (1) | Questionable (2) | Definite, Outside Central Subfield (3) | Definite, Central Subfield Involved (4) | |
| (n = 29) | (n = 7) | (n = 5) | (n = 157) | |
| Mean (SE)a | 67.2 (3.13) | 60.0 (4.85) | 58.6 (8.65) | 55.0 (1.19) |
| Difference (95% CI) vs 1b | — | 3.4 (−12.6, 19.4) | 9.8 (−8.4, 28.1) | 7.2 (−0.9, 15.4) |
| P value vs 1 | — | .947 | .504 | .103 |
| Difference (95% CI) vs 2 | — | — | 6.4 (−15.8, 28.7) | 3.9 (−10.8, 18.5) |
| P value vs 2 | — | — | .876 | .903 |
| Difference (95% CI) vs 3 | — | — | — | −2.6 (−20.1, 15.0) |
| P value vs 3 | — | — | — | .981 |
| Baseline Cystoid Spaces |
||||
| Change from Baseline in BCVA at Week 24 | Central Subfield Not Involved | Central Subfield Involved | ||
|
| ||||
| (n = 39) | (n = 150) | |||
| Mean (SE)a | 5.5 (1.85) | 13.7 (1.12) | ||
| Difference (95% CI)c | — | −6.3 (−11.2, −1.4) | ||
| P value | — | .012 | ||
| Change from Baseline in Cystoid Spaces at Week 24 |
||||
| Change From Baseline in BCVA at Week 24 | Any Improvement | No Improvement or Worsening | ||
|
| ||||
| (n = 79) | (n = 106) | |||
| Mean (SE)a | 16.6 (1.33) | 9.3 (1.15) | ||
| Difference (95% CI)d | — | 7.3 (3.8, 10.8) | ||
| P value | — | <.001 | ||
BCVA = best-corrected visual acuity; CI = confidence interval; CST = central subfield retinal thickness; SE = standard error of the mean.
Note: Spectral-domain optical coherence tomography images with reading center grades of “cannot grade” are excluded from the analysis.
Values represent the sample mean and sample SE within each group.
Between-group differences and 95% CIs are based on the least square means derived from an analysis of covariance model with baseline BCVA as the dependent variable, the baseline cystoid spaces grade as the independent variable, and baseline CST and age as covariates. P values are adjusted using the Tukey-Kramer method for multiple comparisons.
Between-group differences and 95% CIs are based on the least square means derived from an analysis of covariance model with change from baseline in BCVA at week 24 as the dependent variable, the baseline cystoid spaces grade as the independent variable, and baseline BCVA, baseline CST, and age as covariates.
Between-group differences and 95% CIs are based on the least square means derived from an analysis of covariance model with change from baseline in BCVA at week 24 as the dependent variable, the change from baseline in cystoid spaces as the independent variable, and baseline BCVA, baseline CST, and age as covariates.
TABLE 6.
Association Between Best-Corrected Visual Acuity and Presence and Location of Subretinal Fluid.
| Variable | Baseline Presence of Subretinal Fluid |
|||
|---|---|---|---|---|
| Baseline BCVA, letters | Absent (1) | Questionable (2) | Definite, Outside Central Subfield (3) | Definite, Central Subfield Involved (4) |
| (n = 123) | (n = 14) | (n = 0) | (n = 60) | |
| Mean (SE)a | 58.4 (1.53) | 55.3 (5.16) | — | 54.7 (1.53) |
| Difference (95% CI) vs 1b | — | 3.1 (−7.4, 13.7) | — | 3.8 (−2.1, 9.6) |
| P value vs 1 | — | .761 | — | .289 |
| Difference (95% CI) vs 2 | — | — | — | 0.6 (−10.5, 11.7) |
| P value vs 2 | — | — | — | .990 |
| Baseline Subretinal Fluid |
||||
| Change from Baseline in BCVA at Week 24 | Central Subfield Not Involved | Central Subfield Involved | ||
|
| ||||
| (n = 129) | (n = 59) | |||
| Mean (SE)a | 9.5 (1.16) | 17.2 (1.73) | ||
| Difference (95% CI)c | — | −8.2 (−12.4, −4.0) | ||
| P value | — | <.001 | ||
| Change From Baseline in Subretinal Fluid at Week 24 |
||||
| Change from Baseline in BCVA at Week 24 | Any Improvement | No Improvement or Worsening | ||
|
| ||||
| (n = 58) | (n = 124) | |||
| Mean (SE)a | 18.5 (1.70) | 9.0 (1.11) | ||
| Difference (95% CI)d | — | 9.5 (5.3, 13.8) | ||
| P value | — | <.001 | ||
BCVA = best-corrected visual acuity; CI = confidence interval; CST = central subfield retinal thickness; SE = standard error of the mean.
Note: Spectral-domain optical coherence tomography images with reading center grades of “cannot grade” are excluded from the analysis.
Values represent the sample mean and sample SE within each group.
Between-group differences and 95% CIs are based on the least square means derived from an analysis of covariance model with baseline BCVA as the dependent variable, the baseline subretinal fluid grade as the independent variable, and baseline CST and age as covariates. P values are adjusted using the Tukey-Kramer method for multiple comparisons.
Between-group differences and 95% CIs are based on the least square means derived from an analysis of covariance model with change from baseline in BCVA at week 24 as the dependent variable, the baseline subretinal fluid grade as the independent variable, and baseline BCVA, baseline CST, and age as covariates.
Between-group differences and 95% CIs are based on the least square means derived from an analysis of covariance model with change from baseline in BCVA at week 24 as the dependent variable, the change from baseline in subretinal fluid as the independent variable, and baseline BCVA, baseline CST, and age as covariates.
ASSOCIATION BETWEEN BASELINE BCVA AND OCT ANATOMY:
Analyses of the association between baseline BCVA and baseline OCT anatomy included data from 144 eyes with gradable central subfield EZ status, 198 eyes with gradable central subfield cystoid spaces, and 197 eyes with gradable central subfield SRF. Figure 1 summarizes the baseline relationships between these anatomic parameters and BCVA. In the pooled data, mean BCVA at baseline was greatest in eyes with an EZ status of normal (64.6 letters) and progressively worsened as the EZ deteriorated to a nadir of 38.4 letters in eyes with an EZ status of definitely abnormal (absent). Comparisons between eyes with definitely abnormal (absent) EZ grades and each of the other 3 grades were statistically different after adjusting for multiple comparisons (P ≤ .050), as detailed in Table 4. At baseline, EZ accounted for 23.5% of the total variation in BCVA. When baseline CST and age were included as covariates in the model, it rose to 29.1%, as reported in Table 7.
FIGURE 1.
Scatter plots showing baseline relationships between anatomic features and best-corrected visual acuity (BCVA). A. Ellipsoid zone status and Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA at baseline. B. Presence and location of cystoid spaces and ETDRS BCVA at baseline. C. Presence and location of subretinal fluid and ETDRS BCVA at baseline. Mean values are plotted along with 95% CIs. Note: There were no patients with subretinal fluid graded as definite, outside central subfield.
TABLE 7.
Coefficients of Determination From Analysis of Variance/Analysis of Covariance Models.
| Anatomy | Baseline BCVA and Anatomy |
Change From Baseline in BCVA and Anatomy |
||
|---|---|---|---|---|
| Model | R2 (%) | Model | R2 (%) | |
| Central subfield thickness | Multiple linear regression | 14.9 | Multiple linear regression | 33.3 |
| Simple linear regression | 14.6 | Simple linear regression | 17.5 | |
| Ellipsoid zone integrity | ANCOVA | 29.14 | ANCOVA | 24.28 |
| ANOVA | 23.45 | ANOVA | 1.05 | |
| Presence and location of | ||||
| Cystoid spaces | ANCOVA | 17.44 | ANCOVA | 25.52 |
| ANOVA | 7.63 | ANOVA | 6.08 | |
| Subretinal fluid | ANCOVA | 15.42 | ANCOVA | 26.66 |
| ANOVA | 1.26 | ANOVA | 10.05 | |
ANOVA = analysis of variance; ANCOVA = analysis of covariance; BCVA = best-corrected visual acuity; CST = central subfield retinal thickness; EZ = ellipsoid zone integrity.
Note: The coefficient of determination (R2) is the proportion of the variance that is predicted from the independent variables. For CST at baseline, the multiple linear regression included baseline BCVA as the dependent variable and baseline CST and age as the independent variables. The simple linear regression included baseline BCVA as the dependent variable and baseline CST as the independent variable. For the baseline EZ, cystoid spaces and subretinal fluid data, the ANCOVA model included baseline BCVA as the dependent variable, the baseline optical coherence tomography anatomy as the independent variable, and baseline CST and age as the covariates. The ANOVA model included baseline BCVA as the dependent variable and baseline optical coherence tomography anatomy as the independent variable. For CST at week 24, the multiple linear regression included change from baseline BCVA as the dependent variable, and baseline BCVA, baseline CST, age and change from baseline CST as the independent variables. The simple linear regression included change from baseline BCVA as the dependent variable and change from baseline CST as the independent variable. For the week 24 EZ, cystoid spaces and subretinal fluid data, the ANCOVA model included the change from baseline BCVA as the dependent variable, the change from baseline in OCT anatomy as the independent variable, and baseline BCVA, baseline CST, and age as the covariates. The ANOVA model included the change from baseline BCVA as the dependent variable and the change from baseline in optical coherence tomography anatomy as the independent variable.
With respect to cystoid spaces at baseline, 157 of 198 eyes showed definite central subfield involvement. Mean BCVA at baseline ranged from a high in eyes absent of cystoid spaces (67.2 letters) to a low in eyes with definite central subfield involvement (55.0 letters). None of the differences in mean BCVA between central subfield grades in cystoid spaces at baseline achieved statistical significance. Data are summarized in Table 5. At baseline, central subfield cystoid spaces accounted for 7.6% of the total variation in BCVA. This value rose to 17.4% when baseline CST and age were added to the model as covariates, as reported in Table 7.
Of 197 eyes, 123 showed absence of central subfield SRF at baseline; in addition, no eyes showed definite SRF outside the central subfield. Mean BCVA varied little across the SRF gradations, ranging from 58.4 letters in eyes without SRF at one end of the spectrum to 54.7 letters in eyes with definite central subfield involvement at the other end of the spectrum. None of the pair-wise comparisons for SRF achieved statistical significance. Data are summarized in Table 6. At baseline, SRF accounted for 1.3% of the total variation in BCVA. When baseline CST and age as covariates were included in the model, this value rose to 15.4%, as summarized in Table 7.
ASSOCIATION BETWEEN 24-WEEK CHANGES IN BCVA AND BASELINE OCT ANATOMY:
Analyses of the change from baseline in BCVA at week 24 and baseline OCT anatomy included data from 136 eyes for central subfield EZ status, 189 eyes for central subfield cystoid spaces, and 188 eyes for central subfield SRF. Figure 2 summarizes the relationships between these baseline central subfield anatomic features and 24-week BCVA change. Eyes with normal central subfield EZ at baseline experienced a greater improvement in BCVA compared with those eyes with EZ considered not normal by the reading center (11.9 letters vs 9.4 letters, respectively; P = .006). In contrast, eyes without central subfield cystoid spaces at baseline showed less improvement at 24 weeks compared with those eyes with central subfield involvement (5.5 letters vs 13.7 letters, respectively; P = .012). Similarly, eyes without central subfield SRF at baseline showed less improvement at 24 weeks compared with those eyes with central subfield involvement (9.5 letters vs 17.2 letters, respectively; P < .001).
FIGURE 2.
Scatter plots show the relationships between baseline anatomic features and 24-week best-corrected visual acuity (BCVA) change. A. Ellipsoid zone status at baseline and change in Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) at week 24. B. Presence and location of cystoid spaces at baseline and change in ETDRS BCVA at week 24. C. Presence and location of subretinal fluid at baseline and change in ETDRS BCVA at week 24. Mean values are plotted along with 95% CIs.
ASSOCIATION BETWEEN 24-WEEK CHANGES IN BCVA AND 24-WEEK CHANGES IN OCT ANATOMY:
There were 133 eyes with BCVA and EZ change from baseline values at 24 weeks, 185 eyes with BCVA and central subfield cystoid spaces values, and 182 with both BCVA and central subfield SRF values. Figure 3 summarizes the relationships between 24-week change in these anatomic features and 24-week BCVA change. Eyes showing any improvement in EZ status at week 24 experienced a mean change from baseline in BCVA that was numerically greater compared with those that did not show any change from baseline or worsened, but this difference was not statistically significant (11.4 letters vs. 10.0 letters, respectively; P = .512). The change in EZ, when dichotomized into any improvement vs no change or any worsening, accounted for 1.1% of the total variation in the change from baseline in BCVA. When the covariates of baseline BCVA, baseline CST and age were added to the model, then 24.3% of the total variation was accounted for in the change in BCVA, as reported in Table 7.
FIGURE 3.
Scatter plots show the relationships between 24-week change in anatomic features and 24-week best-corrected visual acuity (BCVA) change. A. Change in ellipsoid zone status and change in Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA at week 24. B. Change in presence and location of cystoid spaces and change in ETDRS BCVA at week 24. C. Change in presence and location of subretinal fluid and change in ETDRS BCVA at week 24. Mean values are plotted along with 95% CIs.
In contrast to the EZ status, eyes that showed any improvement in central subfield cystoid spaces and/or central subfield SRF showed a significantly greater improvement in BCVA (16.6 letters and 18.5 letters, respectively) compared with those that did not show any change or worsened from baseline (9.3 letters and 9.0 letters; both P < .001). The change from baseline in central subfield cystoid spaces accounted for 6.1% of the total variation in the change in BCVA, while the change in central subfield SRF accounted for 10.1%. Adding baseline BCVA, baseline CST, and age as covariates to the model increased these percentages to 25.5% and 26.7%, respectively, as reported in Table 7.
LONGITUDINAL RESPONSE MODEL:
A total of 1305B CVA observations and 1291 CST values across all time points from 198 individual patient eyes were available at the beginning of this response analysis. Over time, the modeled BCVA response increased with treatment up to a maximal value, while the modeled CST response decreased with treatment down to a maximum drop. After CLS-TA therapy, the time frame of response was more rapid for CST than for BCVA. Specifically, CST required approximately 3 weeks to reach more than 90% of full response (noted at week 24), whereas BCVA required approximately 9 weeks to reach the same magnitude of response. These modeled full response values were +11.3 letters for BCVA and −114.9 μm for CST. These results are depicted in Figure 4.
FIGURE 4.
Typical modeled Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) and central subfield retinal thickness (CST) responses from active CLS-TA therapy based on the final saturated exponential response models. Curves show a typical improvement of 11.3 letters in BCVA and 114.9 μm in CST at Week 24 from a typical patient given that patient’s baseline ETDRS BCVA and CST values of 53.2 letters and 480.0 μm, respectively.
The maximal BCVA response to therapy for each individual patient was most influenced by the BCVA value at baseline; eyes with lower visual acuity at baseline tended to have the largest improvements, consistent with a ceiling effect. Analysis revealed that the maximal decrease in CST response for each individual patient was significantly influenced by the baseline CST score. In general, the reduction in CST was greater in patients who entered the studies with greater CST at baseline, consistent with a floor effect.
ASSOCIATION BETWEEN EARLY ANATOMIC RESPONSE AND BCVA RESPONSE:
Assessment of BCVA was performed in patients receiving SC-administered CLS-TA, with a baseline CST ≥300 μm and who showed an early anatomic response, defined as a CST reduction of ≥50 μm at 4 weeks after initial treatment compared with baseline. These results are depicted in Figure 5. Early anatomic response was noted in 77 of 111 qualifying patients. Eyes that showed an early anatomic response experienced a greater 24-week improvement in BCVA compared with those without an early response (14.6 vs 6.5 letters, P = .006 for difference). Of note, the early responders did show worse mean baseline CST (506.5 μm) compared with those without an early response (403.8 μm).
FIGURE 5.
Association between early anatomic response and best-corrected visual acuity (BCVA) response. Mean ± SE change from baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA letter score by central subfield retinal thickness (CST) response at week 4. Patients received CLS-TA administered suprachoroidally and had a baseline CST of ≥300 μm. Patients experiencing a reduction from baseline in CST of ≥50 μm at week 4 were classified as responders; otherwise, they were classified as limited responders. Baseline BCVA: 55.1 letters for responders and 61.0 letters for limited responders. Intention-to-treat population; last observation carried forward imputation. Differences between the responders and limited responders were significant at each visit. Difference and P value based on an analysis of variance with response status and pooled country as fixed effects.
DISCUSSION
This study assessed the relationship between BCVA and central subfield OCT findings and temporal features in patients with or without ME due to NIU. There are few previous large studies examining the correlation between BCVA and OCT-determined macular thickness in patients with ME related to NIU. In the Multicenter Uveitis Steroid Treatment (MUST) trial comparing the fluocinolone acetonide implant to systemic therapy, involving 128 eyes with NIU-ME, BCVA and CST showed a moderate negative correlation at baseline (r = −0.56), and change in BCVA showed a moderate negative correlation with change in CST at 6 months (r = −0.46).8 Another study, which included the same pooled patient population as the current analysis, reported low to moderate negative correlation between BCVA and CST (r = −0.38) at baseline, with CST accounting for only 14.6% of the total variation in BCVA.4 Similarly, there was a moderate negative correlation in the 24-week change from baseline values (r = −0.42), with change in CST accounting for only 17.5% of the total variation in the change in BCVA.4 Acute and chronic NIU-ME showed similar baseline and 24-week change correlations.4 Also, BCVA and CST showed similar baseline correlations in NIU-ME, DME, and RVO-related ME, but slightly greater 24-week change correlation in NIU-ME vs DME but not RVO-related ME.4
The current study further expands on anatomic and temporal biomarkers in NIU-ME, the most common cause of visual loss in NIU.10 Integrity of the EZ, also known as the photoreceptor IS/OS junction, reflects anatomic arrangement of photoreceptor outer segments and shows functional correlation in ME due to RVO, DME, and NIU.14–19 The current study demonstrated that mean baseline BCVA progressively worsened with deteriorating central subfield EZ grade in eyes with NIU. In addition, eyes with a normal baseline central subfield EZ experienced meaningfully greater 24-week change in BCVA compared with eyes with abnormal (questionably abnormal, definitely abnormal (patchy), definitely abnormal (absent)) baseline central subfield EZ. Interestingly, a study of adalimumab in 56 eyes of 42 NIU patients assessed extent of EZ disruption and noted no significant association between EZ disruption and BCVA at baseline, but an association when assessed across visits.19 These studies suggest that baseline EZ status has prognostic implications for NIU-ME and may help predict a given patient’s response to therapy.
This study also assessed the association between BCVA and the presence and location of central subfield cystoid spaces or subretinal fluid. While mean BCVA progressively worsened with each central subfield EZ grade at baseline, these trends were not as strongly evident for central subfield cystoid spaces or SRF gradations. However, eyes with baseline central subfield involved cystoid spaces and/or SRF showed a significantly greater BCVA improvement at 24 weeks compared with those eyes without central subfield involvement. Consequently, central subfield cystoid spaces or SRF were not negative prognostic features in these patients with NIU-ME. It is intriguing that eyes with normal baseline central subfield EZ improved more than those with abnormal baseline central subfield EZ, whereas eyes without cystoid spaces and/or SRF in the central subfield at baseline improved less that those with central subfield involvement, possibly suggesting a floor effect for these latter 2 parameters.
Given the limited correlations between BCVA and OCT at fixed time points, this current study assessed their evolving relationships with mathematical modeling for longitudinal change in patients with NIU with or without ME. This study quantitated how BCVA response increased over time with CLS-TA treatment up to a maximal value, and the CST response decreased over time with CLS-TA treatment down to a maximal drop. As expected, analysis revealed that the maximal response in BCVA and CST was influenced by ceiling and floor effects, respectively. However, CST response appeared faster than BCVA, requiring approximately 3 weeks to reach more than 90% of full response, whereas BCVA required approximately 9 weeks to reach the same degree of response. This suggests CST change precedes BCVA response by up to 6 weeks in NIU patients treated with CLS-TA, information that is helpful during patient counseling. Similarly, CLS-TA–treated patients with significant ME at baseline and an early CST response (≥50 μm improvement by 4 weeks) demonstrated better BCVA response at 24 weeks compared with those who did not show an early response, a temporal OCT feature that may have some prognostic utility.
A limitation of this analysis is its post hoc design. As another limitation, while there were inclusion criteria with respect to BCVA in both studies and CST in PEACHTREE, there were no specific entry criteria for other OCT anatomic outcomes. In addition, a limitation of grading the central subfield anatomic features (EZ, cystoid spaces, SRF) into discrete, 4-level categories may provide low sensitivity for detecting change compared with using continuous measures. Finally, this study did not assess other OCT parameters known to have structure-function correlation such as disorganization of retinal inner layers.
The strengths of this analysis include the use of clinical trial data, involving monitor-verified diagnoses per eligibility criteria, protocol refraction, study-certified imagers, and OCT reading center assessment at standardized intervals. Furthermore, there was a broad range of BCVAs and CSTs, including 26 patient eyes that showed CST <300 μm at baseline. Except for the longitudinal and early treatment response analyses, baseline correlations, as well as the relationship between change from baseline in both BCVA and OCT anatomic outcome at 24 weeks, were assessed, regardless of treatment assignment.
In conclusion, this analysis assessed the relationship between OCT anatomic and temporal biomarkers in NIU-ME, using clinical trial data, involving monitor-verified diagnoses per eligibility criteria, protocol refractions, study-certified imagers, and OCT reading center assessment. While there is moderate correlation between BCVA and CST, both at baseline and for change from baseline to 24 weeks, there are additional important clinically relevant relationships between BCVA and OCT anatomic and temporal features in patients with NIU-ME. For central subfield EZ, at baseline, mean BCVA progressively worsened with each EZ grade. Compared with eyes with abnormal baseline EZ, eyes with normal EZ experienced greater 24-week change in BCVA. In contrast, eyes with baseline central subfield cystoid spaces and/or SRF showed more improvement at 24 weeks compared with those eyes without central subfield cystoid spaces and/or SRF. However, the anatomic features described in this study account for a minority of BCVA variation. Longitudinal modeling in NIU patients treated with CLS-TA showed that the frame of response was more rapid for CST than BCVA; as demonstrated, improvement in ME preceded improvement in BCVA. CST required approximately 3 weeks to reach >90% of full response, whereas BCVA required approximately 9 weeks to reach the same magnitude of response. CLS-TA–treated eyes that showed an early anatomic CST response experienced a greater 24-week improvement in BCVA compared with those without an early response.
Supplementary Material
Acknowledgments
Funding/Support:
This project was funded by Clearside Biomedical.
Financial Disclosures:
Thomas A. Ciulla and Barry R. Kapik are both employees of Clearside Biomedical and own stock in the company. Mark R. Barakat reports personal fees from Alcon, Allegro Ophthalmics, Allergan, Alimera, Bausch & Lomb, Clearside Biomedical, EyePoint Pharmaceuticals, Kodiak Sciences, Genentech, Novartis, Ocular Therapeutix, RegenxBio, Adverum Biotechnologies, Regeneron, Graybug, and Palatin Technologies as well as grants from Novartis and Genentech and equity in NeuBAse and Oxurion. Rahul N. Khurana reports personal fees from Allergan, Apellis, Genentech, Alkahest, Regeneron, Merck, Bausch & Lomb, and Aerie as well as grants from Allergan, Apellis, Chengdu Kanghong, Roche, Clearside Biomedical, Graybug, and RegenxBio. Quan Dong Nguyen reports personal fees from Bayer, Clearside Biomedical, Genetech, Roche, Renegeron, and Santen as well as grants from Genetech, Regeneron, and Santen. Dilraj S. Grewal reports personal fees from Novartis, Genentech, and Eyepoint Pharmaceuticals. Thomas Albini reports personal fees from Adverum Biotechnologies, Allergan, Applied Genetic Technologies Corporation, Beaver Visitec, Clearside Biomedical, Eyepoint Pharmaceuticals, Genetech, Notal Vision, Novartis, RegenxBio, and Valeant Pharmaceuticals. The other authors indicate no financial support or conflicts of interest. All authors attest that they meet the current ICMJE criteria for authorship..
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