Clinical trial NCT03161652: Effect of Levosulpiride on Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema
Official title: Clinical Trial to Evaluate the Safety and Efficacy of Levosulpiride to Improve Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Diabetic Macular Edema
Diabetic Retinopathy
Keywords: diabetic retinopathy
blindness
eye
macular edema
prolactin
dopamine antagonists
peptide hormones
Lead sponsor: Universidad Nacional Autonoma de Mexico
Sponsor class: OTHER
Collaborators: name: Instituto Mexicano de Oftalmologia (IMO)
name: Universidad Autónoma de Querétaro
name: General Hospital Nuremberg & Paracelsus Medical University Nuremberg
name: Instituto de la Retina del Bajio SC (INDEREB)
name: Instituto de Neurobiología, Universidad Nacional Autonoma de Mexico (UNAM)
First posted: 2017-05-22
Enrollment: 120
Sex: ALL
Minimum age (years): 40
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The study investigates a medication causing hyperprolactinemia (levosulpiride) to treat diabetic retinopathy (DR) and diabetic macular edema (DME). Subjects are from four different populations, those with DME, non-proliferative DR, those undergoing vitrectomy due to proliferative DR, and those with DME plus standard intravitreal antiangiogenic therapy with ranibizumab. Immediately after baseline, each of the four groups are randomly split into two subgroups: one receiving placebo (sugar pill) and the other levosulpiride. Ophthalmologic and health outcomes between groups 1 and 2 (DME: placebo and levosulpiride), 3 and 4 (DR: placebo and levosulpiride), and 7 and 8 (DME plus ranibizumab: placebo and levosulpiride) evaluate the efficacy and safety of the study medication. Comparison of serum and vitreous prolactin levels between the groups undergoing vitrectomy (DR: placebo and levosulpiride) serve as a proof of principle that prolactin enters the eye to counteract disease progression.
Primary purpose: TREATMENT

Brief summary: This is a randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of levosulpiride to improve retinal alterations due to diabetic macular edema and diabetic retinopathy

Detailed description: Diabetic retinopathy (DR) and diabetic macular edema (DME) are the primary cause of irreversible blindness and visual impairment in working-age adults. Nearly 80% of patients with diabetes will experience some degree of DR and DME 15-20 years after diagnosis. Altered blood parameters (glucose, lipids, and pressure) influence disease development and progression; however, the combined values of these parameters account for only 10% of the risk of DR. Laser therapy is effective for preserving sight but is poor for reversing visual loss. Anti-angiogenic therapies are effective and less destructive but require frequent intravitreal delivery, which raises the risk of infection and ocular complications. Therefore, the prevention and treatment of DR and DME should include other modifiable factors. Data from preclinical studies support a protective role for the serum levels of the hormone prolactin. The trial investigates a new specific therapy for DR and DME based on elevating the circulating levels of prolactin with the prokynetic, dopamine D2 receptor blocker, levosulpiride. It is a prospective, randomized clinical study in patients with DR and DME in which ophthalmologic and health parameters evaluated before and after starting the study medication will determine the efficacy and safety of treatment.

Patient registries: Patients are enrolled at the time of a routine health care service. The caregiver and patient together, in a standardized uniform manner for every patient, will collect the data. Data collection procedures are clearly described and include protocols, policies, and the formatted listing of all the data elements, their full definitions and validation rules. All personnel involved in data collection are qualified registry trained. The same physicians, laboratory technicians, and graduate students will evaluate and collect the data from all patients. An individual fully knowledgeable of all protocols, policies, procedures, and definitions in the registry will be designated as Accountable for Data Quality. This individual (coordinator) should ensure that all collected data are complete, accurate, and valid. Data logically inconsistent will be confronted to information in external database. Data collected on formatted paper forms are entered into a computer and electronic registries carefully reviewed by a third party to identify missing data, invalid or erroneous entries, and inconsistent data. Any data review activity and remediation efforts will be documented. Amelioration of data problems may include querying the personnel uploading the data, the coordinator, the interviewer, or the patient. The proposed sample size and study duration are the minimum required and are based on biological models of DR and on clinical experience evaluating primary data associated with the study. These parameters may have to be modified to accommodate the sample size required to obtain clinically important differences and their statistical evaluation, access to eligible patients, lack of adherence to therapy at specific calendar dates (holidays), etc. Statistical methods include those evaluating continuous and categorical variables, incidence and prevalence, the association between a risk factor and outcome, and the relative contribution of confounding factors.

Eligibility criteria: Inclusion Criteria:

* Age equal or greater than 40 years but no older than 69 years
* Male and female subjects with mild and moderate diabetic macular edema (DME), non-proliferative diabetic retinopathy (DR), and with proliferative DR undergoing medically prescribed vitrectomy.
* Signing informed consent
* Without ocular complications: severe myopia (\> 6 diopters), ocular media opacity, retinal detachment, etc.
* Without previous ocular treatments: ocular surgeries, retinal laser photocoagulation, intravitreal administration of antiangiogenic agents (delivered \< 6 months before enrollment).
* Prolactin serum levels ≤ 20 ng/ml
* With normal or mild loss of kidney function (glomerular filtration rate \>60 ml/min) for groups with DME and DR without vitrectomy.
* With mild to severe loss of kidney function (glomerular filtration rate \>30 ml/min) for groups with DR undergoing vitrectomy.
* Without contraindications for the use of levosulpiride (Parkinson disease, epilepsy, breast cancer, alcoholism, hypokalemia).
* Without hyperprolactinemia inducing conditions: Pathologies (hypothyrodism, hepatic dysfunction, prolactinomas); Medication (antipsychotics, antidepressants, prokinetics, other)

Exclusion Criteria:

* Not meeting inclusion criteria.
* Adverse and intolerable drug effects.
* Not complying with study medication
* Inability to continue in-hospital appointments.
* Missing outcome data
* Hesitation to continue with study medication
* Relocation to another state or country
* Voluntary withdrawal of consent

Primary outcomes:
measure: Visual acuity
timeFrame: 5 minutes
measure: Retinal thickness
timeFrame: Pupils are dilated (eye drops) for 10 to 15 minutes and optical coherence tomography (OCT) images recorded during 5 minutes.
measure: Retinal hard exudates and hemorrhages
timeFrame: Pupils are dilated (eye drops) for 10 to 15 minutes and fundus images recorded during 5 minutes
measure: Retinal microaneurisms, leakage area, cotton-wool spots, venous beading, microvascular and vascular abnormalities
timeFrame: Pupils are dilated (eye drops) for 10 to 15 minutes and fundus images recorded before and at different times (0.5 to 5 minutes) after fluorescein injection.
measure: Prolactin serum levels
timeFrame: 1-2 minutes (duration of blood withdrawal)
measure: Prolactin vitreous levels
timeFrame: 2 minutes (duration of vitreous withdrawal during medically prescribed vitrectomy)
measure: Vasoinhibin vitreous levels
timeFrame: 2 minutes (duration of vitreous withdrawal during medically prescribed vitrectomy)
Secondary outcomes:
measure: Pyruvic glutamic transaminase (TGP) and thyroid stimulating hormone (TSH) serum levels
timeFrame: 1-2 minutes (duration of blood withdrawal)
measure: Blood glycated hemoglobin and creatinine serum levels
timeFrame: 1-2 minutes (duration of blood withdrawal)
measure: Blood pressure
timeFrame: 5 minutes
Other outcomes:
Locations:
city: Querétaro City
country: Mexico
facility: Instituto de la Retina del Bajio SC (INDEREB)
state: Queretaro
city: Queretaro
country: Mexico
facility: Instituto Mexicano de Oftalmologia (IMO)
Study officials:
affiliation: Universidad Nacional Autonoma de Mexico (UNAM)
name: Carmen Clapp, Ph.D.
role: STUDY_DIRECTOR
affiliation: Universidad Autónoma de Querétaro
name: Ludivina Robles Osorio, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto de la Retina del Bajio SC (INDEREB)
name: Renata Garcia Franco, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Institute for Clinical Chemistry, Laboratory Medicine and Transfusion Medicine, Nuremberg General Hospital
name: Jakob Triebel, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Mexicano de Oftalmología (IMO)
name: Marlon R Garcia Roa, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Aranda J, Rivera JC, Jeziorski MC, Riesgo-Escovar J, Nava G, Lopez-Barrera F, Quiroz-Mercado H, Berger P, Martinez de la Escalera G, Clapp C. Prolactins are natural inhibitors of angiogenesis in the retina. Invest Ophthalmol Vis Sci. 2005 Aug;46(8):2947-53. doi: 10.1167/iovs.05-0173.
citation: Garcia C, Aranda J, Arnold E, Thebault S, Macotela Y, Lopez-Casillas F, Mendoza V, Quiroz-Mercado H, Hernandez-Montiel HL, Lin SH, de la Escalera GM, Clapp C. Vasoinhibins prevent retinal vasopermeability associated with diabetic retinopathy in rats via protein phosphatase 2A-dependent eNOS inactivation. J Clin Invest. 2008 Jun;118(6):2291-300. doi: 10.1172/JCI34508.
citation: Clapp C, Thebault S, Arnold E, Garcia C, Rivera JC, de la Escalera GM. Vasoinhibins: novel inhibitors of ocular angiogenesis. Am J Physiol Endocrinol Metab. 2008 Oct;295(4):E772-8. doi: 10.1152/ajpendo.90358.2008. Epub 2008 Jun 10.
citation: Arnold E, Rivera JC, Thebault S, Moreno-Paramo D, Quiroz-Mercado H, Quintanar-Stephano A, Binart N, Martinez de la Escalera G, Clapp C. High levels of serum prolactin protect against diabetic retinopathy by increasing ocular vasoinhibins. Diabetes. 2010 Dec;59(12):3192-7. doi: 10.2337/db10-0873. Epub 2010 Sep 7.
citation: Triebel J, Macotela Y, de la Escalera GM, Clapp C. Prolactin and vasoinhibins: Endogenous players in diabetic retinopathy. IUBMB Life. 2011 Oct;63(10):806-10. doi: 10.1002/iub.518. Epub 2011 Sep 13.
citation: Ramirez M, Wu Z, Moreno-Carranza B, Jeziorski MC, Arnold E, Diaz-Lezama N, Martinez de la Escalera G, Colosi P, Clapp C. Vasoinhibin gene transfer by adenoassociated virus type 2 protects against VEGF- and diabetes-induced retinal vasopermeability. Invest Ophthalmol Vis Sci. 2011 Nov 21;52(12):8944-50. doi: 10.1167/iovs.11-8190.
citation: Arnold E, Thebault S, Baeza-Cruz G, Arredondo Zamarripa D, Adan N, Quintanar-Stephano A, Condes-Lara M, Rojas-Piloni G, Binart N, Martinez de la Escalera G, Clapp C. The hormone prolactin is a novel, endogenous trophic factor able to regulate reactive glia and to limit retinal degeneration. J Neurosci. 2014 Jan 29;34(5):1868-78. doi: 10.1523/JNEUROSCI.2452-13.2014.
citation: Arredondo Zamarripa D, Diaz-Lezama N, Melendez Garcia R, Chavez Balderas J, Adan N, Ledesma-Colunga MG, Arnold E, Clapp C, Thebault S. Vasoinhibins regulate the inner and outer blood-retinal barrier and limit retinal oxidative stress. Front Cell Neurosci. 2014 Oct 20;8:333. doi: 10.3389/fncel.2014.00333. eCollection 2014.
citation: Diaz-Lezama N, Wu Z, Adan-Castro E, Arnold E, Vazquez-Membrillo M, Arredondo-Zamarripa D, Ledesma-Colunga MG, Moreno-Carranza B, Martinez de la Escalera G, Colosi P, Clapp C. Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1. Lab Invest. 2016 Mar;96(3):283-95. doi: 10.1038/labinvest.2015.135. Epub 2015 Nov 16.
citation: Melendez Garcia R, Arredondo Zamarripa D, Arnold E, Ruiz-Herrera X, Noguez Imm R, Baeza Cruz G, Adan N, Binart N, Riesgo-Escovar J, Goffin V, Ordaz B, Pena-Ortega F, Martinez-Torres A, Clapp C, Thebault S. Prolactin protects retinal pigment epithelium by inhibiting sirtuin 2-dependent cell death. EBioMedicine. 2016 May;7:35-49. doi: 10.1016/j.ebiom.2016.03.048. Epub 2016 Apr 20.
citation: Robles-Osorio ML, Garcia-Franco R, Nunez-Amaro CD, Mira-Lorenzo X, Ramirez-Neria P, Hernandez W, Lopez-Star E, Bertsch T, Martinez de la Escalera G, Triebel J, Clapp C. 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. Front Endocrinol (Lausanne). 2018 May 29;9:242. doi: 10.3389/fendo.2018.00242. eCollection 2018.