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Photographic Measures of Cytomegalovirus Retinitis as Surrogates for Visual Outcomes in Treated Patients
Arch Ophthalmol. 2001;119:554-563.
ABSTRACT
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Objective To evaluate photographic measures of cytomegalovirus (CMV) retinitis
as surrogate outcomes for changes in vision in patients with CMV retinitis
related to the acquired immunodefiency syndrome.
Methods Data from 3 clinical trials of CMV retinitis treatments were analyzed.
Two photographic assessments of retinitis in eyes involved at baseline were
evaluated: progression (lesion border movement  750 µm or occurrence
of a new lesion) and change in area of retina involved with retinitis. Vision
measures were decline in best-corrected visual acuity and change in visual
field. Photographic measures were evaluated as surrogate outcomes based on
4 criteria: (1) association with vision measure; (2) ability to account for
treatment-related differences in vision measure; (3) data completeness; and
(4) sample size requirements.
Results Data from 1001 involved eyes (666 patients) were analyzed. Progression
and change in area involved were predictive of declines in vision measures,
accounted for 50% and 66% of the treatment effect on visual field, and were
available from 93% and 64% of involved eyes, respectively. Sample size estimates
for a clinical trial were smallest with progression as the design outcome.
Conclusion Progression and change in area involved met the first and second criteria
for surrogate outcomes for visual field loss; a complete evaluation for visual
acuity decline was not possible because treatment-related differences were
not observed. Progression met the logistical and sample size criteria better
than change in area of retina involved with retinitis.
INTRODUCTION
PIVOTAL EFFICACY trials supporting the approval of treatments for cytomegalovirus
(CMV) retinitis were designed to compare time to retinitis progression as
assessed from photographs between patients randomly assigned to immediate
treatment or to deferral of treatment.1-6
Retinitis progression was defined as 750 µm or more of movement along
the border of an existing lesion or the appearance of a new lesion in either
eye. Assessments of progression made from photographs by graders unaware of
treatment assignment have proven to be a more reliable and sensitive method
than assessments made by clinicians based on ophthalmoscopic examinations.2, 7-8 Movement of 750 µm
or more is a sensitive measure of retinitis advancement selected to protect
patients assigned to deferral of therapy from clinically important vision
loss.
The goal of retinitis treatment is to preserve vision. Despite the widespread
use of photographic assessments of retinitis progression as a primary outcome
measure in clinical trials, it has not been evaluated as a surrogate outcome
for change in vision. The purpose of the current study was to evaluate progression
as well as an alternative retinitis measure assessed from photographs, change
in area of retina involved with retinitis, as surrogate outcomes for declines
in visual acuity and visual field.
Prentice and others have proposed criteria by which to evaluate proposed
surrogate outcomes.9-12
To evaluate the retinitis measures as surrogates for changes in vision, we
operationalized those criteria as follows: (1) association to vision loss;
(2) the degree to which the measure accounted for treatment-related differences
in vision measures; (3) completeness of data; and (4) sample size requirements.
The first 2 criteria evaluate the association between a surrogate and a clinical
outcome in general and with respect to treatment-related changes in these
measures, respectively. The final criteria are related to the feasibility
and practicality of the surrogate outcome.
Data from 3 clinical trials conducted by the Studies of Ocular Complications
of AIDS Research Group were analyzed (Foscarnet-Ganciclovir CMV Retinitis
Trial [FGCRT], the CMV Retinitis Retreatment Trial [CRRT], and the Monoclonal
Antibody CMV Retinitis Trial [MACRT]).8, 13-15
Patients with newly diagnosed retinitis or relapsed retinitis enrolled in
these trials over a 7-year period (1990-1996).
MATERIALS AND METHODS
TRIAL PROTOCOLS
The protocols for all 3 trials were reviewed and approved by institutional
review boards at the coordinating center and at the clinical centers; all
patients signed institutional review board–approved consent statements.
Details on the study designs, procedures, and results are described elsewhere.8, 13-17
PHOTOGRAPHIC MEASURES OF RETINITIS
For these analyses, progression was defined as the movement of a border
750 µm or greater along a front 750 µm or more in length, or the
occurrence of a new lesion 750 µm or greater in diameter and separated
from a previous lesion by 750 µm or more, in a previously uninvolved
eye. Fundus Photograph Reading Center (FPRC) graders unaware of treatment
assignment assessed progression by comparison of photographs taken at baseline
to those taken at follow-up visits.
The extent of retinitis was evaluated from fundus photographs by measuring
the area of retina with retinitis in zones 1 and 2; zone 3 was not evaluated
because it could not be photographed reliably. The definition of retinal zones
has been described.18 Area of retina involved
was expressed as a percentage (ie, area of retina in zones 1 and 2 with retinitis
divided by total area of retina in zones 1 and 2). In the FGCRT, retinal area
involved was determined by FPRC graders from planimetric measurements on a
digitized mosaic of the retina created from fundus photographs.19
In the CRRT and the MACRT, FPRC graders evaluated the area of retina involved
using grids superimposed on the photographs.
VISION MEASURES
The vision measures were visual acuity as measured on logarithmic charts
developed for the Early Treatment Diabetic Retinopathy Study20
and visual field as measured via kinetic perimetry along 12 meridians on a
Goldmann Visual Field Test with a IV4e test object; the degrees of field seen
along each meridian were summed to calculate the visual field score.21
ANALYSIS
Data collected at visits that occurred during the first year of follow-up
before or after the treatment protocols were suspended were included in these
analyses.
For most analyses, data were limited to eyes with CMV retinitis at baseline
as determined from FPRC evaluation of photographs. Baseline characteristics
of involved eyes were summarized from standardized evaluations of photographs
by FPRC graders as previously described.20
For the MACRT, initial treatment for CMV retinitis was defined as the primary
treatment recorded at the baseline visit. Time-dependent variables for the
retinitis measures (progression status and change in retinal area involved
with retinitis) were defined as the value at the same visit at which vision
measures were evaluated or at the most recent prior visit. For progression,
once the event occurred the value of the time-dependent variable did not change.
For event-type measures (progression and visual acuity decline), median
times to event were estimated according to the Kaplan-Meier method and Cox
proportional hazards models were used to estimate relative risks (RRs).22-23 For baseline characteristics, P values associated with RRs of events were derived using
procedures for estimating variance of correlated data (2 eyes from 1 patient).24 No corrections for correlated data were made for
models including time-dependent covariates. Continuous outcomes were modeled
with linear regression using general estimating equation procedures, which
accounted for correlations among repeated observations from an eye.25 Analyses of associations of retinitis measures to
vision measures were performed by trial and stage of retinitis (newly diagnosed
or relapsed) because of the large variability in event rates across trials.
If appropriate, data were combined for overall estimates of the associations.
The capacity of a retinitis measure to account for the treatment effect
on visual field was evaluated by comparing the linear regression coefficient
for CMV treatment estimated from a model without the time-dependent retinitis
measure with those from a model that included the measure.9, 12
The deviance scores (-2 log likelihood statistics) were used to compare
the predictive value of the retinitis measures for visual acuity decline and
visual field decline.23, 26 These
analyses were performed on the subgroup of involved eyes for which data on
all measures of retinitis were available.
Sample size estimates were made for event-type outcomes with log rank
tests and for continuous outcomes with t test procedures.27-28 Because of secular trends in event
rates and mean changes, event rates, means, and SDs were estimated based on
MACRT data.
RESULTS
BASELINE CHARACTERISTICS OF PATIENTS
Two hundred thirty-four patients with newly diagnosed retinitis were
enrolled in the FGCRT; 279 patients with relapsed retinitis were enrolled
in the CRRT; 209 patients (83 patients with newly diagnosed retinitis and
126 with relapsed retinitis) were enrolled in the MACRT. The analyses presented
herein included data from 88% to 95% of patients enrolled in these trials
(ie, those patients who had baseline and follow-up photographic data available
for at least 1 eye with CMV retinitis at baseline) (Table 1). Eight patients were enrolled in more than 1 of the trials;
separate data were collected for each trial in which they were enrolled.
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Table 1. Patient Characteristics at Baseline*
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Patients enrolled in the 3 trials had similar demographic profiles with
the exception that relatively more whites were enrolled in the FGCRT (Table 1). Relatively more patients enrolled
in the most recent trial, the MACRT, received combinations of antiretrovirals,
and those were the only patients who received protease inhibitors at baseline.
Patients enrolled in the first 2 trials were assigned to an anti-CMV treatment.
Patients enrolled in the last trial selected their primary anti-CMV treatment
and were most likely to have received intravenous (IV) ganciclovir as their
primary treatment at baseline.
BASELINE CHARACTERISTICS OF EYES WITH RETINITIS
Characteristics of involved eyes that were different among the trials
after adjustment for stage of retinitis were zone 1 involvement, activity,
and microangiopathy (hemorrhage/microaneurysms and cotton-wool spots) (Table 2). Involved eyes of patients with
newly diagnosed retinitis had smaller, more active lesions and greater percentages
with cotton-wool spots, vitreous hemorrhage, and retinitis involvement of
the optic disc than involved eyes of patients with relapsed retinitis (Table 2).
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Table 2. Characteristics of Involved Eyes at Baseline*
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PROGRESSION IN INVOLVED EYES
Data to evaluate progression in involved eyes were available for 88%
to 96% of involved eyes of patients enrolled in the 3 trials. Median times
to progression differed among the 3 trials (Table 3) (P = .001) (Figure 1), but were similar for eyes of newly diagnosed and relapsed
retinitis after adjustment for trial and initial CMV treatment (Table 3) (P = .19).
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Table 3. Measures of Retinitis and Vision During Follow-up*
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Figure 1. Kaplan-Meier curves for time to
progression and visual acuity (VA) decline in involved eyes by trial and stage
of retinitis. Progress was defined as lesion border progression of 750 µm
or more or occurrence of a new lesion as assessed by the Fundus Photograph
Reading Center. Visual acuity loss was defined as a decline of VA of 15 or
more standard letters on an Early Treatment of Diabetic Retinopathy Study
chart. A, Foscarnet-Ganciclovir CMV [cytomegalovirus] Retinitis Trial (FGCRT):
progress, 251 events in 318 involved eyes of 224 patients; VA loss, 142 events
in 302 involved eyes of 215 patients. B, CMV Retinitis Retreatment Trial (CRRT):
progress, 266 events in 403 involved eyes of 256 patients; VA loss, 176 events
in 392 involved eyes of 259 patients. C, Monoclonal Antibody CMV Retinitis
Trial (MACRT), newly diagnosed: progress, 61 events in 100 involved eyes of
73 patients; VA loss, 28 events in 100 involved eyes of 74 patients. D, MACRT,
newly diagnosed: progress, 114 events in 188 involved eyes of 120 patients;
VA loss, 58 events in 180 involved eyes of 119 patients.
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Initial treatment for CMV retinitis was not associated with risk of
progression in the FGCRT (IV ganciclovir vs IV foscarnet), but was associated
in the CRRT (P<.001) and MACRT (P = .007). In the CRRT, the median times to first progression while
receiving treatment in involved eyes were 2.5, 2.0, and 5.1 months for the
IV ganciclovir, IV foscarnet, and IV combination treatment groups, respectively.
In the MACRT, the median times to first progression were 2.7, 6.2, and 5.8
months for patients receiving IV or oral systemic monotherapy, IV combination
therapy, or local therapy, respectively.
AREA OF RETINA (ZONES 1 AND 2) WITH RETINITIS IN INVOLVED EYES
Data to evaluate the percentage of retinal area involved with retinitis
at baseline and during follow-up were available for 55% to 68% of involved
eyes. The mean rates of change in retinal area involved with retinitis, expressed
as a percentage of zones 1 and 2, for the first 6 months of follow-up differed
among the trials (Table 3) (P<.001): the rates were 3.5%, 2.6%, and 1.4% of retinal
area per month in the FGCRT, CRRT, and MACRT, respectively. Change in area
during follow-up was similar for eyes of patients with newly diagnosed and
relapsed retinitis (Table 3) (P = .81).
Change in the percentage of retinal area involved with retinitis was
related to treatment for CMV retinitis in the MACRT (P<.001),
and there was a suggestion that it was in the CRRT (P
= .08), but not in the FGCRT (Table 3).
In the CRRT, IV ganciclovir therapy was associated with a mean increase in
the percentage of retinal area involved with retinitis over the first 6 months
of follow-up of 1.9% compared with IV combination therapy; IV foscarnet was
associated with an increase of 1.3% compared with IV ganciclovir. For example,
the estimated mean increases in retinal area involved after 6 months of follow-up
were 15.2%, 13.3%, and 16.5% for IV ganciclovir, IV combination, and IV foscarnet,
respectively. In the MACRT, IV or oral systemic monotherapy was associated
with a mean increase of 5.2% as compared with IV combination therapy and an
increase of 4.6% as compared with local therapy. After 6 months, the mean
increases in retinal area with retinitis for involved eyes of newly diagnosed
patients were 10.1%, 4.9%, and 5.4% for monotherapy, IV combination therapy,
and local therapy, respectively.
VISUAL ACUITY DECLINE IN INVOLVED EYES
Visual acuity results from follow-up were available on 88% to 94% of
involved eyes. After adjustment for stage of retinitis and initial treatment
for CMV, the median times to decline in visual acuity of 15 letters or more
on an Early Treatment Diabetic Retinopathy Study chart (eg, going from 20/20
to 20/40 in Snellen equivalents) differed among the trials (Table 3) (P = .02) (Figure 1). Involved eyes of patients with newly diagnosed and relapsed
retinitis had similar risks of events (Table 3) (P = .45). Initial treatment for
CMV retinitis did not influence the risk of visual acuity decline in any of
the trials (Table 3).
VISUAL FIELD CHANGE IN INVOLVED EYES
Visual field data were available on 64% to 82% of involved eyes. The
rate of visual field loss differed among the 3 trials (Table 3) (P<.001). However, the rate
of visual field loss was similar for involved eyes of patients with newly
diagnosed and relapsed retinitis (Table
3) (P = .46).
In the FGCRT and CRRT, visual field loss during follow-up was not associated
with initial treatment for CMV retinitis (Table 3). In the MACRT, there were treatment-related differences
in visual field loss for all involved eyes (P = .01)
(Table 3). Initial treatment with
IV systemic combination therapy was associated with a smaller decline in visual
field over follow-up (mean, 48.0° less) than the decline in the IV or
oral systemic monotherapy group. Local therapy also tended to be associated
with a smaller overall decline in visual field than in the systemic monotherapy
group (mean, 27.4° less). The estimated mean decreases in visual field
for involved eyes of patients with newly diagnosed retinitis over 12 months
were 117.0°, 69.1°, and 89.0° for monotherapy, IV combination
therapy, and local therapy, respectively.
ASSOCIATIONS BETWEEN RETINITIS MEASURES AND VISUAL ACUITY LOSS
Overall, progression was associated with about a doubling of the risk
of a decline in visual acuity of 15 or more letters (Table 4) (RR = 2.1, P<.001), and the
increase in risk did not differ across trials (Table 4) (P = .86) or by stage of retinitis
(Table 4) (P = .27).
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Table 4. Associations Between Measures of Retinitis and Vision*
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The associations of change in the percentage of retinal area (zones
1 and 2) involved with retinitis to decline in visual acuity of 15 or more
letters were similar across groups defined by stages of retinitis (Table 4) (P =
.62) but differed among the trials (Table
4) (P = .001). In the FGCRT and MACRT,
a 10% increase in area involved with retinitis was associated with a 1.3 (P<.001) and 1.9 (combined MACRT data, P = .01) increase in the risk of the event, but there was no association
of change in area with visual acuity decline in the CRRT.
The strength of the associations of time-dependent retinitis measures
to visual acuity decline were compared based on the deviance score (-2
log likelihood statistic); larger deviance scores indicated that the retinitis
measure explained more of the variability in the outcome. Because the patterns
of missing data were different for each retinitis measure, the deviance scores
were calculated for the subgroup of eyes for which data on all retinitis measures
were available, effectively those with data on retinal area involved. The
RRs for each time-dependent retinitis measure estimated from these subgroups
were consistent with the RRs estimated from all available data (data not shown).
Change in area of retina involved with retinitis was more predictive of visual
acuity decline than progression in the FGCRT and MACRT (Table 4). In the CRRT, progression was more predictive than change
in area.
ASSOCIATIONS BETWEEN RETINITIS MEASURES AND VISUAL FIELD LOSS
Overall, the average decline in visual field associated with retinitis
progression was 75.1° (Table 4)
(P<.001). The associations were not different
across trials (Table 4) (P = .53) or by stage of retinitis (Table 4) (P = .86).
Change in the percentage of retinal area involved also was associated
with change in visual field (Table 4)
(Figure 2). Overall, the average
decline in visual field associated with an increase of retinal area involved
by 10% was 52.1° (Table 4)
(P<.001). The associations were similar across
trials (Table 4) (P = .25), but tended to be larger for involved eyes of relapsed patients
(Table 4) (P = .06).
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Figure 2. Change in visual field by change
in retinal area with retinitis for involved eyes of patients enrolled by trial
and stage of retinitis. A, Foscarnet-Ganciclovir CMV [cytomegalovirus] Retinitis
Trial (FGCRT): dots represent 573 observations from 207 involved eyes of 152
patients with newly diagnosed retinitis at baseline. Line is estimated as
the change in field (°) = 13.8° + (6.0°/% x change in area
[%]). B, CMV Retinitis Retreatment Trial (CRRT): dots represent 465 observations
from 238 involved eyes of 162 patients with relapsed retinitis at baseline.
Line is estimated as the change in field (°) = 47.8° + (5.8°/%
x change in area [%]). C, Monoclonal Antibody CMV Retinitis Trial (MACRT),
newly diagnosed: dots represent 124 observations from 60 involved eyes of
47 patients with newly diagnosed retinitis. Line is estimated as the change
in field (°) = 19.4° + (4.3°/% x change in area [%]). D,
MACRT, relapsed: dots represent 225 observations from 112 involved eyes of
77 patients with relapsed retinitis at baseline. Line is estimated as the
change in field (°) = 21.4° + (6.8°/% x change in area [%]).
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The strength of the associations between retinitis measures and visual
field loss were compared with deviance scores. In all groups, change in area
of retina involved with retinitis was more predictive of decline in visual
field than progression (Table 4).
ASSOCIATION BETWEEN TREATMENT EFFECTS ON RETINITIS AND VISION MEASURES
In these analyses the only observed treatment effect on a vision measure
was in the MACRT. Systemic combination therapy was associated with a smaller
decline in visual field than systemic monotherapy. To evaluate how much of
the treatment-related differences in visual field were accounted for by an
intermediate retinitis measure (ie, progression or change in area involved),
the treatment effect on visual field was estimated in models without and with
a covariate for the time-dependent retinitis measure (Table 5). In model 1, which does not include a time-dependent retinitis
measure, systemic combination therapy was associated with a smaller loss of
visual field (mean, 48.0° less), than treatment with systemic monotherapy.
Inclusion of progression as a time-dependent covariate in the model (model
2) resulted in a 50% reduction in the average treatment effect associated
with combination systemic treatment (ie, from -48.0° to -23.9°),
and the treatment effect was no longer significant. Inclusion of change in
area of retina involved with retinitis in the model (model 3) resulted in
a 66% reduction of the treatment effect, and the effect was no longer significant.
Therefore, each measure accounted for some of the treatment-related differences
in visual field, but change in area seemed to capture more of the effect.
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Table 5. Treatment Effect on Visual Field With and Without Time-Dependent
Retinitis Measurement (Monoclonal Antibody CMV [Cytomegalovirus] Retinitis
Trial)
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SAMPLE SIZE
Estimates of the sample size required to detect 50% differences in outcome
(ie, an RR of 1.5 or a 50% change in continuous measure), for a clinical trial
of 2 treatments were 182 patients for progression, 226 for change in area
involved with retinitis, 312 for visual acuity loss (15 letters), and
352 for change in visual field.
COMMENT
The criteria used to evaluate measures of retinitis as surrogate outcomes
for visual function measures were how well the measure predicted changes in
visual function, how well treatment-related changes in vision outcomes were
accounted for by changes in the measure, the completeness of data collection,
and the sample size required for trials. Results for the 2 measures are summarized
in Table 6.
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Table 6. Summary of Evaluation of Retinitis Measures as Surrogate Outcomes
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Change in retinal area involved was more predictive of visual acuity
decline for involved eyes than progression (Table 4). However, the association was not uniform; it was not associated
with visual acuity decline in the involved eyes of patients with relapsed
retinitis enrolled in the CRRT. On average, these eyes had the largest area
involved with retinitis, and the highest rate of inner zone 1 involvement
(Table 2). Therefore, relatively
small increases in retinal area involved may have had detrimental effects
on visual acuity thereby attenuating the association. Change in area involved
with retinitis was a stronger predictor of visual field decline than progression
and the associations were uniform across trials and by stage of retinitis
(Table 4).
In the MACRT, change in area of retina involved with retinitis accounted
for a larger portion of the treatment effect on visual field (66%) than progression
(50%) (Table 5). Although the
confidence intervals on these proportions may be large,11-12
the ranking is likely to be correct and is consistent with the observed associations
of the retinitis measures to visual field loss (Table 4). Area of retina involved is a continuous measure able to
incorporate both spatial and temporal aspects of retinitis spread, unlike
the threshold measurement of progression.
Even with up to 1 year of follow-up, observed treatment effects on retinitis
measures were not uniformly followed by treatment effects on visual function
measures. Does the lack of consistent treatment effects on both types of measures
indicate that retinitis measures are not good surrogate outcomes? We think
not. Effects on visual acuity are likely to be influenced by location of retinitis.
Eyes with retinitis in zone 1 are more likely to lose visual acuity regardless
of the status of retinitis measures (data not shown). Furthermore, the Studies
of Ocular Complications of AIDS protocols included safeguards against visual
acuity loss that made it less likely that treatment-related differences would
be observed. In the CRRT, a treatment effect on visual field was observed
in the primary results of the trial.14 That
analysis included all data collected before protocol suspension, whereas the
present analysis included data collected during the first year of follow-up,
regardless of whether the visits occurred before or up to 6 months after the
protocol was suspended. The latter approach may have emphasized incongruities
between treatment effects on retinitis and vision measures because of treatment
modifications during follow-up. In the CRRT, patients assigned to the combination
of IV ganciclovir and foscarnet were more likely to have treatment-related
toxic effects and switch to monotherapy,14
and patients receiving monotherapy who progressed were likely to receive combination
therapy, especially after the treatment protocol was suspended. These results
highlight another potential advantage of a valid surrogate outcome—the
ability to measure treatment response before irreparable harm to the patient
occurs.
Data on progression were available for at least 1 follow-up visit for
most involved eyes (93% overall), whereas available data on area of retina
involved with retinitis were fewer (64% overall). Two factors that contributed
to that high rate of missing data were less frequent assessments of retinal
area involved and photograph quality. Area assessments were done less frequently
because they required more time. Photograph quality is more critical for evaluating
retinal area involved because the 10 photographs must overlap appropriately
to document all of zones 1 and 2, and all of the photographs must be of good
quality. Data on retinal area involved from 19% of photograph sets were not
used because more than 10% of zones 1 and 2 could not be graded, whereas only
9% of photograph sets could not be graded for progression.
The sample size estimates were smallest for trials with progression
as the design outcome, which required 13% fewer patients than if change in
area involved was the design outcome and at least 40% fewer than required
for change in visual function. Change in area involved with retinitis is less
efficient because of the relatively large variance of the measure.
Overall, retinitis progression in an involved eye fulfilled the criteria
outlined for a surrogate outcome better than change in area involved with
retinitis (Table 6). Progression
was associated with all measures of decline in visual function and the associations
were uniform across all groups of patients; it accounted for, in part, the
treatment effect on the clinical outcome of visual field decline; relatively
complete data collection was achievable; and the sample size required for
a trial was reduced.
There is an obvious relationship between the retinitis measures evaluated
and vision—if more retina is destroyed, vision is lost. However, even
in this situation, these measures were imperfect surrogates for vision. Progression
and change in retinal area involved accounted for only part of the treatment-related
change in visual field and did not reflect long-term visual outcomes. Patients
without progression lost vision because of other causes, such as retinal detachments.
These data suggest that retinitis progression is a reasonable outcome for
small trials evaluating the efficacy of new treatments; however, larger trials
evaluating the relative efficacy of treatments should include measures of
visual acuity and field.
AUTHOR INFORMATION
Accepted for publication September 7, 2000.
Supported by cooperative agreements from the National Eye Institute,
Bethesda, Md, to the School of Hygiene and Public Health (U10 EY 08057, 1
R03 EY10731-01, NRSA EY07127) and School of Medicine (U10 EY 08052), Johns
Hopkins University, Baltimore, Md, and the University of Wisconsin School
of Medicine, Madison (U10 EY 08067). Additional support provided by National
Center for Research Resources, through General Clinical Research Center grants
5M01 RR 00350 (Baylor College of Medicine, Houston, Tex); 5M01 RR 00035 and
5M01 RR 00722 (Johns Hopkins University); 5M01 RR 05096 (Louisiana State University/Tulane,
New Orleans); 5M01 RR 00071 (Mt Sinai Medical Center, New York, NY); 5M01
RR 00047 (New York Hospital-Cornell Medical Center, New York); 5M01 RR 00096
(New York University, New York); 5M01 RR 00048 (Northwestern University, Evanston,
Ill); 5M01 RR 00865 (University of California, Los Angeles); 5M01 RR 00083
(University of California, San Francisco); 5M01 RR 05280 (University of Miami,
Miami, Fla); and 5M01 RR 00046 (University of North Carolina, Chapel Hill).
Support also provided by the National Institute of Allergy and Infectious
Diseases, Bethesda, Md, through cooperative agreements U01 AI 27668 (Johns
Hopkins University); U01 AI 27674 (Louisiana State University/Tulane); U01
AI 27669 (Memorial Sloan-Kettering, New York, NY); and U01 AI 25917 (New York
Hospital-Cornell Medical Center); U01 AI 27667 (Mount Sinai Medical Center);
U01 AI 27665 (New York University); U01 AI 25915 (Northwestern University);
U01 AI 27660 (University of California, Los Angeles); U01 AI 27670 (University
of California, San Diego); U01 AI 27663 (University of California, San Francisco);
and U01 AI 25868 (University of North Carolina). Funding was also provided
by Astra Pharmaceutical Products Inc (Westborough, Mass) and Protein Design
Laboratories Inc (Mountain View, Calif).
Drugs were provided by Amgen Inc (Thousand Oaks, Calif), Astra Pharmaceutical
Products Inc, Bristol-Myers Squibb Co (Princeton, NJ), Burroughs Wellcome
Co (Research Triangle Park, NC), Syntex Research (Palo Alto, Calif), and Protein
Design Laboratories Inc, Plymouth, Minn.
The membership of the Studies of Ocular Complications of AIDS Research
Group is listed in prior articles reporting results of these trials.7, 15-16
Corresponding author: Janet T. Holbrook, PhD, MPH, 615 N Wolfe St,
Room 5010, Baltimore, MD 21205 (e-mail: jholbroo{at}jhsph.edu).
Janet T. Holbrook, PhD, MPH;
Curtis L. Meinert, PhD;
Mark L. Van Natta, MHS;
Matthew Davis, MD;
Larry Hubbard, MA;
Douglas A. Jabs, MD, MBA;
for the Studies of Ocular Complications of AIDS Research Group
From the Center for Clinical Trials (Drs Holbrook and Meinert and Mr
Van Natta) and the Departments of Ophthalmology and Medicine (Dr Jabs), Johns
Hopkins University, Baltimore, Md; and the Fundus Photograph Reading Center,
University of Wisconsin, Madison (Dr Davis and Mr Hubbard).
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