Baseline characteristics of a cohort within a clinical trial are shaped by the eligibility criteria. Nevertheless, many of the baseline demographic characteristics of this DRCR.net cohort, who were specifically enrolled in a treatment trial of DME, are similar to those reported for other cohorts enrolled in large phase 3 studies evaluating diabetic retinopathy (though not specifically DME) including the ETDRS, (N=3711) and the PKC-DRS2 (a recent trial which evaluated ruboxistaurin for diabetic retinopathy, N=685).12, 13
Similarities include the duration of diabetes and the racial/ethnic profile of the participants.12, 13
However, the age of participants in this DRCR.net cohort is slightly older than the ETDRS (48% of study participants were under age 50) and the PKC-DRS2 cohort (mean age 59 years, range 23 – 87 years). The ETDRS specifically excluded individuals who were age 70 and older; whereas nearly one quarter of this DRCR.net cohort is in this age group. Therefore, when the results from this study are available, they will reflect a population of diabetic patients that is older compared with the cohorts recruited for the ETDRS and the PKC-DRS2.12, 13
The PKC-DRS2 did not have a ceiling on the maximum age of participants during their recruitment period of 2001 and 2005, yet the PKC-DRS2 cohort was younger than our cohort. This DRCR.net trial required the presence of center involving DME confirmed by OCT whereas the PKC-DRS2 did not have this requirement. One-half of the PKC-DRS2 subjects had either no DME or retinal thickening that was more than 500 microns from the foveal center implying an earlier stage in the disease process and therefore a greater probability of a younger subject age.
This DRCR.net cohort was recruited between 2004 and 2006 from a geographically diverse and large number of clinical centers, therefore, the characteristics of this group may be more indicative of the type of individuals expected to enroll in contemporary clinical trials that focus on center-involved DME. Furthermore, participants in this current DRCR.net trial were enrolled without contemporaneous eligibility review from the RC and all but 29 (3%) of the participants met the inclusion criteria following the RC review of baseline images. Therefore, the results of this trial may be generalized to similar patient populations at large identified to have DME by a retina specialist.
Another important distinguishing baseline characteristic of this cohort relative to other trials is the level of glycemic control as reflected in glycosylated hemoglobin levels. The mean HbA1C is 7.9 in this DRCR.net study with 10% of subjects having a value of 10.0 or higher. In contrast, the mean level of HbA1C was 8.1 in the PKC-DRS2 and in the ETDRS 42% of participants had a HbA1C ≥10.0. While unknown confounding factors could account for these differences, we presume that improved systemic control of the DM will result in a cohort at lower risk and slower rate of progression of their retinopathy which may indicate a more benign natural course of their DME and potentially a different treatment response.14, 15
The lower glycosylated hemoglobin levels in this DRCR.net cohort relative to the ETDRS cohort may also be an indicator of more optimal management of other systemic factors that relate to severity of diabetes complications such as hypertension and lipid levels. In this regard, the majority of our participants also reported receiving treatment for hypertension and hypercholesterolemia. Since systemic control of DM may affect DME, the importance of using concurrent controls rather than historical controls from other clinical trials, is highlighted.
Individuals could only participate in this DRCR.net study if their VA was between 20/40 and 20/320 Snellen equivalent. Participants and investigators were willing to randomize eyes at the better end of this VA spectrum to either focal/grid photocoagulation or intravitreal triamcinolone as 19% of the study eyes had a VA letter score between 69 and 73 inclusive (Snellen equivalent of 20/40) and 43% had a VA letter score between 59 and 68 inclusive (Snellen equivalent of 20/50 to 20/63). In comparison with other large phase 3 studies for diabetic retinopathy, the baseline VA of this DRCR.net cohort is lower (median letter score of 62 letters, 20/63). However, this may be the result of different inclusion criteria for VA between studies. Subjects were permitted in this trial with VA letter scores between 24 and 74 inclusive. In contrast, the range of permissible VA letter scores was ≥34 in the ETDRS and >45 in the PKC-DRS2 which were associated with mean baseline VA letter scores of approximately 80 in the ETDRS and 77 in the PKC-DRS2. The lower initial VA in this DRCR.net cohort may allow a better opportunity to determine if either treatment intervention (intravitreal triamcinolone or focal/grid photocoagulation) provides for an increase in VA letter score of 15 or more although this may be tempered by the possibility that subjects with lower initial VA letter scores may be refractory to treatment due to factors such as ischemia or chronic macular edema.
This DRCR.net study will provide an opportunity to evaluate several ocular characteristics that have not been fully evaluated in any other phase 3 studies for DME, namely retinal thickness and retinal thickening as measured by OCT. This cohort had a median CST of 401 microns, representing a moderate degree of retinal thickening. A very wide range of retinal thickness is represented with nearly equal fractions of mild, moderate, and severe thickening measurements. Similar to results from a DRCR.net study of diabetic patients with little or no retinopathy and no clinical evidence of center involved DME16
, men in this study had larger CST values than women (median 419 vs. 383 microns). Qualitative assessment of the OCT images at the RC also demonstrated anatomical abnormalities such as moderate to severe cystoid abnormalities present in 34% and subfoveal subretinal fluid in 19% of participants. Notably, 33% of participants were assessed by the RC as having questionable or definite vitreoretinal interface abnormalities at baseline. The frequency with which the RC identified these changes is important since investigators were asked to exclude potential participants who had macular edema from any cause other than DME which may have included clinically apparent vitreo-retinal interface abnormalities. Outcomes of the treatment interventions will be explored in each of these OCT based subgroups to determine their influence on treatment effect.
Baseline demographic, systemic and ocular characteristics by self-reported race were evaluated. This DRCR.net cohort (72% white) is similar to the ETDRS (76% white) and the PKC-DRS2 (78% white) in racial demographic. No substantial differences were identified between any of the racial subgroups for any of the baseline variables; however, this analysis is limited by the small number of participants in this DRCR.net cohort who are categorized as non-white.
Comparison of several demographic, systemic and ocular characteristics by participant age led to the following observations: older participants were more likely to have type 2 diabetes, have a longer duration of DM and were more likely to be pseudophakic. The distribution of retinopathy severity level favored milder stages of retinopathy and lesser degrees of macular edema among the oldest participants. In particular, subjects 70 years or older were less likely than younger participants to have severe NPDR or PDR, and less likely to have extensive areas of macular retinal thickening or angiographic macular leakage despite having a longer median duration of DM ( and ). A larger proportion of participants in the older subgroup had received laser treatment for DME prior to enrollment when compared with the other age groups and this may explain, in part, the differences in areas of retinal thickening and leakage. However, there also appears to be a difference in retinopathy level between the older subgroup and the other subgroups which would not be explained by differential rates of PRP. These potential relationships between age and retinopathy levels could possibly be explained by a long-term survival hypothesis: individuals with more severe diabetes, as reflected by the severity of diabetic retinopathy, may be more likely to die at an early age such that only those with milder levels of retinopathy live to an older age. In support of this hypothesis, a long term follow-up study of ETDRS participants at one center found that more severe degrees of retinopathy and poorer levels of VA at study entry and close out of the ETDRS increased the odds of subsequent mortality.17
Baseline characteristics of the non-study fellow eye indicate that the majority of participants had their more severely effected eye enrolled into this trial. The reason for this phenomenon is unclear, but may reflect a hesitancy of participating ophthalmologists to enroll the “better seeing” eye and may reflect a referral pattern in which participating ophthalmologists treat mainly patients with asymmetric disease.