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

Ma Ludivina Robles-Osorio, Renata García-Franco, Carlos D Núñez-Amaro, Ximena Mira-Lorenzo, Paulina Ramírez-Neria, Wendy Hernández, Ellery López-Star, Thomas Bertsch, Gonzalo Martínez de la Escalera, Jakob Triebel, Carmen Clapp, Ma Ludivina Robles-Osorio, Renata García-Franco, Carlos D Núñez-Amaro, Ximena Mira-Lorenzo, Paulina Ramírez-Neria, Wendy Hernández, Ellery López-Star, Thomas Bertsch, Gonzalo Martínez de la Escalera, Jakob Triebel, Carmen Clapp

Abstract

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.

Keywords: dopamine receptor type 2 blockers; microvascular alterations; peptide hormones; pituitary hormones; prolactin; ranibizumab; retina; vasoinhibins.

Figures

Figure 1
Figure 1
Study design. ETDRS, Early Treatment Diabetic Retinopathy Study; OCT, optical coherence tomography; HbA1c, glycated hemoglobin; ALT, alanine aminotransferase; TSH, thyroid-stimulating hormone; DME, diabetic macular edema; TID, three times a day; NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy.

References

    1. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet (2010) 376(9735):124–36.10.1016/S0140-6736(09)62124-3
    1. Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care (2012) 35(3):556–64.10.2337/dc11-1909
    1. Klein BE, Knudtson MD, Tsai MY, Klein R. The relation of markers of inflammation and endothelial dysfunction to the prevalence and progression of diabetic retinopathy: Wisconsin epidemiologic study of diabetic retinopathy. Arch Ophthalmol (2009) 127(9):1175–82.10.1001/archophthalmol.2009.172
    1. Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med (2012) 366(13):1227–39.10.1056/NEJMra1005073
    1. Lachin JM, Genuth S, Nathan DM, Zinman B, Rutledge BN, Group DER. Effect of glycemic exposure on the risk of microvascular complications in the diabetes control and complications trial—revisited. Diabetes (2008) 57(4):995–1001.10.2337/db07-1618
    1. Klein R. The epidemiology of diabetic retinopathy. In: Duh EJ, editor. Diabetic Retinopathy. Humana Press; (2008). p. 67–107.10.1007/978-1-59745-563-3
    1. Boyer DS, Hopkins JJ, Sorof J, Ehrlich JS. Anti-vascular endothelial growth factor therapy for diabetic macular edema. Ther Adv Endocrinol Metab (2013) 4(6):151–69.10.1177/2042018813512360
    1. Clapp C, Thebault S, Macotela Y, Moreno-Carranza B, Triebel J, Martinez de la Escalera G. Regulation of blood vessels by prolactin and vasoinhibins. Adv Exp Med Biol (2015) 846:83–95.10.1007/978-3-319-12114-7_4
    1. Triebel J, Bertsch T, Bollheimer C, Rios-Barrera D, Pearce CF, Hufner M, et al. Principles of the prolactin/vasoinhibin axis. Am J Physiol Regul Integr Comp Physiol (2015) 309(10):R1193–203.10.1152/ajpregu.00256.2015
    1. Duenas Z, Torner L, Corbacho AM, Ochoa A, Gutierrez-Ospina G, Lopez-Barrera F, et al. Inhibition of rat corneal angiogenesis by 16-kDa prolactin and by endogenous prolactin-like molecules. Invest Ophthalmol Vis Sci (1999) 40(11):2498–505.
    1. Aranda J, Rivera JC, Jeziorski MC, Riesgo-Escovar J, Nava G, Lopez-Barrera F, et al. Prolactins are natural inhibitors of angiogenesis in the retina. Invest Ophthalmol Vis Sci (2005) 46(8):2947–53.10.1167/iovs.05-0173
    1. Zepeda-Romero LC, Vazquez-Membrillo M, Adan-Castro E, Gomez-Aguayo F, Gutierrez-Padilla JA, Angulo-Castellanos E, et al. Higher prolactin and vasoinhibin serum levels associated with incidence and progression of retinopathy of prematurity. Pediatr Res (2017) 81(3):473–9.10.1038/pr.2016.241
    1. Triebel J, Macotela Y, de la Escalera GM, Clapp C. Prolactin and vasoinhibins: endogenous players in diabetic retinopathy. IUBMB Life (2011) 63(10):806–10.10.1002/iub.518
    1. Triebel J, Huefner M, Ramadori G. Investigation of prolactin-related vasoinhibin in sera from patients with diabetic retinopathy. Eur J Endocrinol (2009) 161(2):345–53.10.1530/EJE-09-0130
    1. Arnold E, Rivera JC, Thebault S, Moreno-Paramo D, Quiroz-Mercado H, Quintanar-Stephano A, et al. High levels of serum prolactin protect against diabetic retinopathy by increasing ocular vasoinhibins. Diabetes (2010) 59(12):3192–7.10.2337/db10-0873
    1. Pan H, Nguyen NQ, Yoshida H, Bentzien F, Shaw LC, Rentier-Delrue F, et al. Molecular targeting of antiangiogenic factor 16K hPRL inhibits oxygen-induced retinopathy in mice. Invest Ophthalmol Vis Sci (2004) 45(7):2413–9.10.1167/iovs.03-1001
    1. Garcia C, Aranda J, Arnold E, Thebault S, Macotela Y, Lopez-Casillas F, et al. Vasoinhibins prevent retinal vasopermeability associated with diabetic retinopathy in rats via protein phosphatase 2A-dependent eNOS inactivation. J Clin Invest (2008) 118(6):2291–300.10.1172/JCI34508
    1. Ramirez M, Wu Z, Moreno-Carranza B, Jeziorski MC, Arnold E, Diaz-Lezama N, et al. Vasoinhibin gene transfer by adenoassociated virus type 2 protects against VEGF- and diabetes-induced retinal vasopermeability. Invest Ophthalmol Vis Sci (2011) 52(12):8944–50.10.1167/iovs.11-8190
    1. Diaz-Lezama N, Wu Z, Adan-Castro E, Arnold E, Vazquez-Membrillo M, Arredondo-Zamarripa D, et al. Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1. Lab Invest (2016) 96(3):283–95.10.1038/labinvest.2015.135
    1. Arredondo Zamarripa D, Diaz-Lezama N, Melendez Garcia R, Chavez Balderas J, Adan N, Ledesma-Colunga MG, et al. Vasoinhibins regulate the inner and outer blood-retinal barrier and limit retinal oxidative stress. Front Cell Neurosci (2014) 8:333.10.3389/fncel.2014.00333
    1. Antonetti DA, Barber AJ, Bronson SK, Freeman WM, Gardner TW, Jefferson LS, et al. Diabetic retinopathy: seeing beyond glucose-induced microvascular disease. Diabetes (2006) 55(9):2401–11.10.2337/db05-1635
    1. Arnold E, Thebault S, Baeza-Cruz G, Arredondo Zamarripa D, Adan N, Quintanar-Stephano A, et al. The hormone prolactin is a novel, endogenous trophic factor able to regulate reactive glia and to limit retinal degeneration. J Neurosci (2014) 34(5):1868–78.10.1523/JNEUROSCI.2452-13.2014
    1. Andrade C. Low-dose amisulpride and elevation in serum prolactin. J Clin Psychiatry (2013) 74(6):e558–60.10.4088/JCP.13f08510
    1. Mansi C, Savarino V, Vigneri S, Perilli D, Melga P, Sciaba L, et al. Gastrokinetic effects of levosulpiride in dyspeptic patients with diabetic gastroparesis. Am J Gastroenterol (1995) 90(11):1989–93.
    1. Kashyap P, Farrugia G. Diabetic gastroparesis: what we have learned and had to unlearn in the past 5 years. Gut (2010) 59(12):1716–26.10.1136/gut.2009.199703
    1. Tonini M, Cipollina L, Poluzzi E, Crema F, Corazza GR, De Ponti F. Review article: clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics. Aliment Pharmacol Ther (2004) 19(4):379–90.10.1111/j.1365-2036.2004.01867.x
    1. Diabetic Retinopathy Clinical Research Network. Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med (2015) 372(13):1193–203.10.1056/NEJMoa1414264
    1. Corcostegui B, Duran S, Gonzalez-Albarran MO, Hernandez C, Ruiz-Moreno JM, Salvador J, et al. Update on diagnosis and treatment of diabetic retinopathy: a consensus guideline of the Working Group of Ocular Health (Spanish Society of Diabetes and Spanish Vitreous and Retina Society). J Ophthalmol (2017) 2017:8234186.10.1155/2017/8234186
    1. Lee SH, Kunz J, Lin SH, Yu-Lee LY. 16-kDa prolactin inhibits endothelial cell migration by down-regulating the Ras-Tiam1-Rac1-Pak1 signaling pathway. Cancer Res (2007) 67(22):11045–53.10.1158/0008-5472.CAN-07-0986
    1. Virgili G, Menchini F, Murro V, Peluso E, Rosa F, Casazza G. Optical coherence tomography (OCT) for detection of macular oedema in patients with diabetic retinopathy. Cochrane Database Syst Rev (2011) (7):CD008081.10.1002/14651858.CD008081.pub2
    1. Wilkinson CP, Ferris FL, III, Klein RE, Lee PP, Agardh CD, Davis M, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology (2003) 110(9):1677–82.10.1016/S0161-6420(03)00475-5
    1. Ioannidis JP, Evans SJ, Gotzsche PC, O’Neill RT, Altman DG, Schulz K, et al. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med (2004) 141(10):781–8.10.7326/0003-4819-141-10-200411160-00009
    1. Chow S, Shao J, Wang H. Sample Size Calculations in Clinical Research. Boca Raton, FL: Chapman & Hall/CRC; (2008).
    1. Wells JA, Glassman AR, Jampol LM, Aiello LP, Antoszyk AN, Baker CW, et al. Association of baseline visual acuity and retinal thickness with 1-year efficacy of aflibercept, bevacizumab, and ranibizumab for diabetic macular edema. JAMA Ophthalmol (2016) 134(2):127–34.10.1001/jamaophthalmol.2015.4599
    1. Guslandi M. The clinical use of levosulpiride. Curr Ther Res (1993) 53(5):484–501.10.1016/S0011-393X(05)80656-3
    1. Lozano R, Concha MP, Montealegre A, de Leon L, Villalba JO, Esteban HL, et al. Effectiveness and safety of levosulpiride in the treatment of dysmotility-like functional dyspepsia. Ther Clin Risk Manag (2007) 3(1):149–55.10.2147/tcrm.2007.3.1.149
    1. Kapur S, Langlois X, Vinken P, Megens AA, De Coster R, Andrews JS. The differential effects of atypical antipsychotics on prolactin elevation are explained by their differential blood-brain disposition: a pharmacological analysis in rats. J Pharmacol Exp Ther (2002) 302(3):1129–34.10.1124/jpet.102.035303
    1. McMurdo ME, Howie PW, Lewis M, Marnie M, McEwen J, McNeilly AS. Prolactin response to low dose sulpiride. Br J Clin Pharmacol (1987) 24(2):133–7.10.1111/j.1365-2125.1987.tb03153.x
    1. Kuchay MS, Mithal A. Levosulpiride and serum prolactin levels. Indian J Endocrinol Metab (2017) 21(2):355–8.10.4103/ijem.IJEM_555_16
    1. Cookson J, Hodgson R, Wildgust HJ. Prolactin, hyperprolactinaemia and antipsychotic treatment: a review and lessons for treatment of early psychosis. J Psychopharmacol (2012) 26(5 Suppl):42–51.10.1177/0269881112442016
    1. Corazza GR, Biagi F, Albano O, Bianchi Porro G, Cheli R, Mazzacca G, et al. Levosulpiride in functional dyspepsia: a multicentric, double-blind, controlled trial. Ital J Gastroenterol (1996) 28(6):317–23.
    1. Poulsen JE. Recovery from retinopathy in a case of diabetes with Simmonds’ disease. Diabetes (1953) 2(1):7–12.10.2337/diab.2.1.7
    1. Powell ED, Frantz AG, Rabkin MT, Field RA. Growth hormone in relation to diabetic retinopathy. N Engl J Med (1966) 275(17):922–5.10.1056/NEJM196610272751703
    1. Plumb M, Nath K, Seaquist ER. Hypopituitarism stabilizes the renal and retinal complications of diabetes mellitus. Am J Nephrol (1992) 12(4):265–7.10.1159/000168456
    1. Cohen SR, Gardner TW. Diabetic retinopathy and diabetic macular edema. Dev Ophthalmol (2016) 55:137–46.10.1159/000438970
    1. Melendez Garcia R, Arredondo Zamarripa D, Arnold E, Ruiz-Herrera X, Noguez Imm R, Baeza Cruz G, et al. Prolactin protects retinal pigment epithelium by inhibiting sirtuin 2-dependent cell death. EBioMedicine (2016) 7:35–49.10.1016/j.ebiom.2016.03.048

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren