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Basis and Design of a Randomized Clinical Trial to Evaluate the Effect of Levosulpiride on Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema
BACKGROUND: Diabetic retinopathy (DR) and diabetic macular edema (DME) are potentially blinding, microvascular retinal diseases in people with diabetes mellitus. Preclinical studies support a protective role of the hormone prolactin (PRL) due to its ocular incorporation and conversion to vasoinhibin...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986911/ https://www.ncbi.nlm.nih.gov/pubmed/29896154 http://dx.doi.org/10.3389/fendo.2018.00242 |
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author | Robles-Osorio, Ma. Ludivina García-Franco, Renata Núñez-Amaro, Carlos D. Mira-Lorenzo, Ximena Ramírez-Neria, Paulina Hernández, Wendy López-Star, Ellery Bertsch, Thomas Martínez de la Escalera, Gonzalo Triebel, Jakob Clapp, Carmen |
author_facet | Robles-Osorio, Ma. Ludivina García-Franco, Renata Núñez-Amaro, Carlos D. Mira-Lorenzo, Ximena Ramírez-Neria, Paulina Hernández, Wendy López-Star, Ellery Bertsch, Thomas Martínez de la Escalera, Gonzalo Triebel, Jakob Clapp, Carmen |
author_sort | Robles-Osorio, Ma. Ludivina |
collection | PubMed |
description | BACKGROUND: Diabetic retinopathy (DR) and diabetic macular edema (DME) are potentially blinding, microvascular retinal diseases in people with diabetes mellitus. Preclinical studies support a protective role of the hormone prolactin (PRL) due to its ocular incorporation and conversion to vasoinhibins, a family of PRL fragments that inhibit ischemia-induced retinal angiogenesis and diabetes-derived retinal vasopermeability. Here, we describe the protocol of an ongoing clinical trial investigating a new therapy for DR and DME based on elevating the circulating levels of PRL with the prokinetic, dopamine D2 receptor blocker, levosulpiride. METHODS: It is a prospective, randomized, double-blind, placebo-controlled trial enrolling male and female patients with type 2 diabetes having DME, non-proliferative DR (NPDR), proliferative DR (PDR) requiring vitrectomy, and DME plus standard intravitreal therapy with the antiangiogenic agent, ranibizumab. Patients are randomized to receive placebo (lactose pill, orally TID) or levosulpiride (75 mg/day orally TID) for 8 weeks (DME and NPDR), 1 week (the period before vitrectomy in PDR), or 12 weeks (DME plus ranibizumab). In all cases the study medication is taken on top of standard therapy for diabetes, blood pressure control, or other medical conditions. Primary endpoints in groups 1 and 2 (DME: placebo and levosulpiride), groups 3 and 4 (NPDR: placebo and levosulpiride), and groups 7 and 8 (DME plus ranibizumab: placebo and levosulpiride) are changes from baseline in visual acuity, retinal thickness assessed by optical coherence tomography, and retinal microvascular abnormalities evaluated by fundus biomicroscopy and fluorescein angiography. Changes in serum PRL levels and of PRL and vasoinhibins levels in the vitreous between groups 5 and 6 (PDR undergoing vitrectomy: placebo and levosulpiride) serve as proof of principle that PRL enters the eye to counteract disease progression. Secondary endpoints are changes during the follow-up of health and metabolic parameters (blood pressure, glycated hemoglobin, and serum levels of glucose and creatinine). A total of 120 patients are being recruited. DISCUSSION: This trial will provide important knowledge on the potential benefits and safety of elevating circulating and intraocular PRL levels with levosulpiride in patients with DR and DME. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Ethics Committees of the National University of Mexico (UNAM) and the Instituto Mexicano de Oftalmología, I.A.P. Dissemination will include submission to peer-reviewed scientific journals and presentation at congresses. CLINICAL TRIAL REGISTRATION: Registered at www.ClinicalTrials.gov, ID: NCT03161652 on May 18, 2017. |
format | Online Article Text |
id | pubmed-5986911 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-59869112018-06-12 Basis and Design of a Randomized Clinical Trial to Evaluate the Effect of Levosulpiride on Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema Robles-Osorio, Ma. Ludivina García-Franco, Renata Núñez-Amaro, Carlos D. Mira-Lorenzo, Ximena Ramírez-Neria, Paulina Hernández, Wendy López-Star, Ellery Bertsch, Thomas Martínez de la Escalera, Gonzalo Triebel, Jakob Clapp, Carmen Front Endocrinol (Lausanne) Endocrinology BACKGROUND: Diabetic retinopathy (DR) and diabetic macular edema (DME) are potentially blinding, microvascular retinal diseases in people with diabetes mellitus. Preclinical studies support a protective role of the hormone prolactin (PRL) due to its ocular incorporation and conversion to vasoinhibins, a family of PRL fragments that inhibit ischemia-induced retinal angiogenesis and diabetes-derived retinal vasopermeability. Here, we describe the protocol of an ongoing clinical trial investigating a new therapy for DR and DME based on elevating the circulating levels of PRL with the prokinetic, dopamine D2 receptor blocker, levosulpiride. METHODS: It is a prospective, randomized, double-blind, placebo-controlled trial enrolling male and female patients with type 2 diabetes having DME, non-proliferative DR (NPDR), proliferative DR (PDR) requiring vitrectomy, and DME plus standard intravitreal therapy with the antiangiogenic agent, ranibizumab. Patients are randomized to receive placebo (lactose pill, orally TID) or levosulpiride (75 mg/day orally TID) for 8 weeks (DME and NPDR), 1 week (the period before vitrectomy in PDR), or 12 weeks (DME plus ranibizumab). In all cases the study medication is taken on top of standard therapy for diabetes, blood pressure control, or other medical conditions. Primary endpoints in groups 1 and 2 (DME: placebo and levosulpiride), groups 3 and 4 (NPDR: placebo and levosulpiride), and groups 7 and 8 (DME plus ranibizumab: placebo and levosulpiride) are changes from baseline in visual acuity, retinal thickness assessed by optical coherence tomography, and retinal microvascular abnormalities evaluated by fundus biomicroscopy and fluorescein angiography. Changes in serum PRL levels and of PRL and vasoinhibins levels in the vitreous between groups 5 and 6 (PDR undergoing vitrectomy: placebo and levosulpiride) serve as proof of principle that PRL enters the eye to counteract disease progression. Secondary endpoints are changes during the follow-up of health and metabolic parameters (blood pressure, glycated hemoglobin, and serum levels of glucose and creatinine). A total of 120 patients are being recruited. DISCUSSION: This trial will provide important knowledge on the potential benefits and safety of elevating circulating and intraocular PRL levels with levosulpiride in patients with DR and DME. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Ethics Committees of the National University of Mexico (UNAM) and the Instituto Mexicano de Oftalmología, I.A.P. Dissemination will include submission to peer-reviewed scientific journals and presentation at congresses. CLINICAL TRIAL REGISTRATION: Registered at www.ClinicalTrials.gov, ID: NCT03161652 on May 18, 2017. Frontiers Media S.A. 2018-05-29 /pmc/articles/PMC5986911/ /pubmed/29896154 http://dx.doi.org/10.3389/fendo.2018.00242 Text en Copyright © 2018 Robles-Osorio, García-Franco, Núñez-Amaro, Mira-Lorenzo, Ramírez-Neria, Hernández, López-Star, Bertsch, Martínez de la Escalera, Triebel and Clapp. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Endocrinology Robles-Osorio, Ma. Ludivina García-Franco, Renata Núñez-Amaro, Carlos D. Mira-Lorenzo, Ximena Ramírez-Neria, Paulina Hernández, Wendy López-Star, Ellery Bertsch, Thomas Martínez de la Escalera, Gonzalo Triebel, Jakob Clapp, Carmen Basis and Design of a Randomized Clinical Trial to Evaluate the Effect of Levosulpiride on Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema |
title | Basis and Design of a Randomized Clinical Trial to Evaluate the Effect of Levosulpiride on Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema |
title_full | Basis and Design of a Randomized Clinical Trial to Evaluate the Effect of Levosulpiride on Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema |
title_fullStr | Basis and Design of a Randomized Clinical Trial to Evaluate the Effect of Levosulpiride on Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema |
title_full_unstemmed | Basis and Design of a Randomized Clinical Trial to Evaluate the Effect of Levosulpiride on Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema |
title_short | Basis and Design of a Randomized Clinical Trial to Evaluate the Effect of Levosulpiride on Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema |
title_sort | basis and design of a randomized clinical trial to evaluate the effect of levosulpiride on retinal alterations in patients with diabetic retinopathy and diabetic macular edema |
topic | Endocrinology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986911/ https://www.ncbi.nlm.nih.gov/pubmed/29896154 http://dx.doi.org/10.3389/fendo.2018.00242 |
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