A step change on the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) may provide a more sensitive and efficient endpoint for detecting the therapeutic efficacy of drugs to treat diabetic retinopathy (DR) during clinical trials, according to findings published in Clinical Ophthalmology.

The DRSS is a standard system for measuring the severity of DR. During clinical trials, the severity of a subject’s retinopathy over time can be categorized into discrete steps on the scale. Many trials require a 2- or 3-step improvement or progression on the DRSS to determine therapeutic merit. However, relatively large sample sizes are needed to reach those efficacy thresholds, particularly when the standard of care is used as the control. This isn’t always feasible in the early stage of drug discovery. Therefore, finding more sensitive and cost-effective endpoints is critical for discovering new drugs to treat DR.

American researchers designed a study to evaluate the sensitivity and statistical efficiency of detecting a drug effect in DR across different DRSS endpoints. A second goal was to find alternative analytical approaches to facilitate smaller DR-related trials before conducting larger trials to confirm results. To do this, the team analyzed simulated data and data from 2 randomized, double-blinded, controlled phase III trials, RIDE (Clinicaltrials.gov Identifier: NCT00473382) and RISE (ClinicalTrials.gov Identifier: NCT00473330). RIDE and RISE are methodologically identical 3-year trials that enrolled a total of 759 patients with decreased vision due to center-involved diabetic macular edema and the presence of macular edema documented on optical coherence tomography.


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Changes in DRSS steps that span a 3 months for patients (n=205) with no active intervention were used to confirm the reliability of DRSS outcomes. A simulation study compared the sensitivity and statistical efficiency across different DRSS endpoints. Investigators found that the standard deviation of step change between the baseline and month 3 DRSS across different steps at baseline were all within 1 step, confirming the reliability of DRSS measure by each step. The efficiency of detecting reliable therapeutic efficacy was amplified when the treatment effect in improvement and progression was evaluated together. The highest level of sensitivity was observed when the change in DRSS steps was used directly as an endpoint.

“Results from this study showed that improved trial efficiency may be achieved by utilizing more efficient analytic approaches for DRSS outcomes through comparing progression and improvement simultaneously, by either combining the binary endpoints or using change in DRSS steps directly,” explains the study.

Disclosure: This study and both of the study’s authors are supported by Genetech. Please see the original reference for a full list of authors’ disclosures.

Reference

Zhang J, Strauss EC. Sensitive detection of therapeutic efficacy with the etdrs diabetic retinopathy severity scale. Clin Ophthalmol. 2020;14:4385-4393. doi:10.2147/OPTH.S286527.