Sensitive Detection of Therapeutic Efficacy with the ETDRS Diabetic Retinopathy Severity Scale

Jiameng Zhang, Erich C Strauss Early Clinical Development, Genentech, Inc, South San Francisco, CA, USACorrespondence: Jiameng ZhangGenentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USAEmail zhang.jiameng@gene.comBackground: The Early Treatment Diabetic Retinopathy Study Diabetic Retinopath...

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Autores principales:	Zhang J, Strauss EC
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	diabetic retinopathy diabetic retinopathy severity scale anti-vegf diabetes Ophthalmology RE1-994
Acceso en línea:	https://doaj.org/article/a39cfecf0bea4b36b89950f1b257868b
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spelling	oai:doaj.org-article:a39cfecf0bea4b36b89950f1b257868b2021-12-02T13:32:05ZSensitive Detection of Therapeutic Efficacy with the ETDRS Diabetic Retinopathy Severity Scale1177-5483https://doaj.org/article/a39cfecf0bea4b36b89950f1b257868b2020-12-01T00:00:00Zhttps://www.dovepress.com/sensitive-detection-of-therapeutic-efficacy-with-the-etdrs-diabetic-re-peer-reviewed-article-OPTHhttps://doaj.org/toc/1177-5483Jiameng Zhang, Erich C Strauss Early Clinical Development, Genentech, Inc, South San Francisco, CA, USACorrespondence: Jiameng ZhangGenentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USAEmail zhang.jiameng@gene.comBackground: The Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (DRSS) is a standard approach to measure diabetic retinopathy (DR) severity. Many clinical trials evaluating drug intervention for DR rely upon demonstration of a therapeutic effect through measurement of a 2- or 3-step improvement or progression on the DRSS; however, these binary endpoints require a relatively large sample size for a reliable estimate of therapeutic efficacy, especially when the SOC (eg, anti-VEGF) is used as a control. This study was designed to evaluate the sensitivity and statistical efficiency of detecting a drug effect in DR across different DRSS endpoints, and present alternative analytical approaches to enable smaller-size DR trials for detecting a reliable efficacy signal before moving into larger confirmatory DR trials.Methods: Data from two randomized, double-blinded, controlled Phase III trials, that enrolled patients with decreased vision due to center-involved DME and the presence of macular edema documented on optical coherence tomography and simulated data, were used for this study. Changes in DRSS steps during a 3-month period from patients (n=205) with no active intervention were used to confirm the reliability of DRSS outcomes. A simulation study compared sensitivity and statistical efficiency across different DRSS endpoints.Results: The standard deviation of step change between baseline and month 3 DRSS across different steps at baseline were all within 1 step, confirming the reliability of DRSS measure by each step. Efficiency of detecting reliable therapeutic efficacy was augmented when treatment effect in improvement and progression was evaluated together; highest sensitivity was observed when change in DRSS steps was used directly as an endpoint.Conclusion: DRSS step change may provide more robust sensitivity and statistical efficiency. It is therefore a more cost-effective endpoint for the detection of therapeutic efficacy signal in drug discoveries in DR.Keywords: diabetic retinopathy, Diabetic Retinopathy Severity Scale, anti-VEGF, diabetesZhang JStrauss ECDove Medical Pressarticlediabetic retinopathydiabetic retinopathy severity scaleanti-vegfdiabetesOphthalmologyRE1-994ENClinical Ophthalmology, Vol Volume 14, Pp 4385-4393 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	diabetic retinopathy diabetic retinopathy severity scale anti-vegf diabetes Ophthalmology RE1-994
spellingShingle	diabetic retinopathy diabetic retinopathy severity scale anti-vegf diabetes Ophthalmology RE1-994 Zhang J Strauss EC Sensitive Detection of Therapeutic Efficacy with the ETDRS Diabetic Retinopathy Severity Scale
description	Jiameng Zhang, Erich C Strauss Early Clinical Development, Genentech, Inc, South San Francisco, CA, USACorrespondence: Jiameng ZhangGenentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USAEmail zhang.jiameng@gene.comBackground: The Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (DRSS) is a standard approach to measure diabetic retinopathy (DR) severity. Many clinical trials evaluating drug intervention for DR rely upon demonstration of a therapeutic effect through measurement of a 2- or 3-step improvement or progression on the DRSS; however, these binary endpoints require a relatively large sample size for a reliable estimate of therapeutic efficacy, especially when the SOC (eg, anti-VEGF) is used as a control. This study was designed to evaluate the sensitivity and statistical efficiency of detecting a drug effect in DR across different DRSS endpoints, and present alternative analytical approaches to enable smaller-size DR trials for detecting a reliable efficacy signal before moving into larger confirmatory DR trials.Methods: Data from two randomized, double-blinded, controlled Phase III trials, that enrolled patients with decreased vision due to center-involved DME and the presence of macular edema documented on optical coherence tomography and simulated data, were used for this study. Changes in DRSS steps during a 3-month period from patients (n=205) with no active intervention were used to confirm the reliability of DRSS outcomes. A simulation study compared sensitivity and statistical efficiency across different DRSS endpoints.Results: The standard deviation of step change between baseline and month 3 DRSS across different steps at baseline were all within 1 step, confirming the reliability of DRSS measure by each step. Efficiency of detecting reliable therapeutic efficacy was augmented when treatment effect in improvement and progression was evaluated together; highest sensitivity was observed when change in DRSS steps was used directly as an endpoint.Conclusion: DRSS step change may provide more robust sensitivity and statistical efficiency. It is therefore a more cost-effective endpoint for the detection of therapeutic efficacy signal in drug discoveries in DR.Keywords: diabetic retinopathy, Diabetic Retinopathy Severity Scale, anti-VEGF, diabetes
format	article
author	Zhang J Strauss EC
author_facet	Zhang J Strauss EC
author_sort	Zhang J
title	Sensitive Detection of Therapeutic Efficacy with the ETDRS Diabetic Retinopathy Severity Scale
title_short	Sensitive Detection of Therapeutic Efficacy with the ETDRS Diabetic Retinopathy Severity Scale
title_full	Sensitive Detection of Therapeutic Efficacy with the ETDRS Diabetic Retinopathy Severity Scale
title_fullStr	Sensitive Detection of Therapeutic Efficacy with the ETDRS Diabetic Retinopathy Severity Scale
title_full_unstemmed	Sensitive Detection of Therapeutic Efficacy with the ETDRS Diabetic Retinopathy Severity Scale
title_sort	sensitive detection of therapeutic efficacy with the etdrs diabetic retinopathy severity scale
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/a39cfecf0bea4b36b89950f1b257868b
work_keys_str_mv	AT zhangj sensitivedetectionoftherapeuticefficacywiththeetdrsdiabeticretinopathyseverityscale AT straussec sensitivedetectionoftherapeuticefficacywiththeetdrsdiabeticretinopathyseverityscale
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Sensitive Detection of Therapeutic Efficacy with the ETDRS Diabetic Retinopathy Severity Scale

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