NCT03161652

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

Trial Health

77
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
120

participants targeted

Target at P50-P75 for phase_2

Timeline
13mo left

Started May 2017

Longer than P75 for phase_2

Geographic Reach
1 country

2 active sites

Status
recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Progress89%
May 2017Jun 2027

First Submitted

Initial submission to the registry

May 18, 2017

Completed
4 days until next milestone

First Posted

Study publicly available on registry

May 22, 2017

Completed
2 days until next milestone

Study Start

First participant enrolled

May 24, 2017

Completed
9.5 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 1, 2026

Expected
6 months until next milestone

Study Completion

Last participant's last visit for all outcomes

June 1, 2027

Last Updated

November 18, 2025

Status Verified

November 1, 2025

Enrollment Period

9.5 years

First QC Date

May 18, 2017

Last Update Submit

November 17, 2025

Conditions

Diabetic Macular EdemaDiabetic Retinopathy

Keywords

diabetic retinopathyblindnesseyemacular edemaprolactindopamine antagonistspeptide hormones

Outcome Measures

Primary Outcomes (7)

  • Visual acuity

    Number of letters recognized in the Early Treatment Diabetic Retinopathy Study (ETDRS) chart test after correcting for any refractive error (myopia, hyperopia, or astigmatism)

    5 minutes

  • Retinal thickness

    Retinal thickness is evaluated by non-invasive optical coherence tomography (OCT) imaging via qualitative and quantitative analyses. For qualitative analyses, OCT images approaching the histological level of retinal morphology are interpreted based on normal and diseased features (hyper-reflective or hypo-reflective lesions, shadowing, and anatomical changes). Quantitative analysis evaluates retinal reflective signals and their correlation with retinal morphology by computer image-processing algorithms (retinal thickness map, volume, area, 1, 3, and 6 mm ETDRS circle diameters).

    Pupils are dilated (eye drops) for 10 to 15 minutes and optical coherence tomography (OCT) images recorded during 5 minutes.

  • Retinal hard exudates and hemorrhages

    Number, size, and location of retinal hard exudates and hemorrhages evaluated by indirect ophthalmoscopy

    Pupils are dilated (eye drops) for 10 to 15 minutes and fundus images recorded during 5 minutes

  • Retinal microaneurisms, leakage area, cotton-wool spots, venous beading, microvascular and vascular abnormalities

    Location, intensity, and source of above alterations evaluated by fundus fluorescein angiography imaging qualitative and quantitative analysis of hyper-fluorescent or hypo-fluorescent regions.

    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.

  • Prolactin serum levels

    ng/ml levels of prolactin quantified in serum samples using the IMMULITE 2000 XPi immunoassay system

    1-2 minutes (duration of blood withdrawal)

  • Prolactin vitreous levels

    ng/ml levels of prolactin quantified in vitreous samples using the IMMULITE 2000 XPi immunoassay system

    2 minutes (duration of vitreous withdrawal during medically prescribed vitrectomy)

  • Vasoinhibin vitreous levels

    Optical density values of vasoinhibins obtained by the immunoprecipitation-Western blot analysis of vitreous samples

    2 minutes (duration of vitreous withdrawal during medically prescribed vitrectomy)

Secondary Outcomes (3)

  • Pyruvic glutamic transaminase (TGP) and thyroid stimulating hormone (TSH) serum levels

    1-2 minutes (duration of blood withdrawal)

  • Blood glycated hemoglobin and creatinine serum levels

    1-2 minutes (duration of blood withdrawal)

  • Blood pressure

    5 minutes

Study Arms (8)

DME lactose pill

PLACEBO COMPARATOR

Patients with DME will be randomized to take a lactose pill (placebo).

Drug: DME lactose pill

DME levosulpiride

EXPERIMENTAL

Patients with DME will be randomized to take levosulpiride.

Drug: DME levosulpiride

DR lactose pill

PLACEBO COMPARATOR

Patients with non-proliferative DR will be randomized to take a lactose pill (placebo)

Drug: DR lactose pill

DR levosulpiride

EXPERIMENTAL

Patients with non-proliferative DR will be randomized to take levosulpiride

Drug: DR levosulpiride

DR, vitrectomy lactose pill

PLACEBO COMPARATOR

Patients with proliferative DR (undergoing medically prescribed vitrectomy 7 days after starting the study) will be randomized to take a lactose pill (placebo).

Drug: DR vitrectomy lactose pill

DR, vitrectomy levosulpiride

EXPERIMENTAL

Patients with proliferative DR (undergoing medically prescribed vitrectomy 7 days after starting the study) will be randomized to take levosulpiride.

Drug: DR vitrectomy levosulpiride

DME plus ranibizumab lactose pill

PLACEBO COMPARATOR

Patients with DME that will receive intravitreal antiangiogenic therapy with ranibizumab will be randomized to take a lactose pill (placebo)

Drug: DME plus ranibizumab lactose pill

DME plus ranibizumab levosulpiride

EXPERIMENTAL

Patients with DME that will receive intravitreal antiangiogenic therapy with ranibizumab will be randomized to take levosulpiride

Drug: DME plus ranibizumab levosulpiride

Interventions

DME lactose pillDRUG

Patients with DME will take placebo orally 3 times a day (TID) for 8 weeks.The placebo is taken on top of standard therapy for diabetes and blood pressure control.

Also known as: placebo, sugar
DME lactose pill
DME levosulpirideDRUG

Patients with DME will take levosulpiride (75 mg/day) orally TID for 8 weeks. Levosulpiride is taken on top of standard therapy for diabetes and blood pressure control.

Also known as: dopamine D2 receptor blocker
DME levosulpiride
DR lactose pillDRUG

Patients with non-proliferative DR will take a lactose pill (placebo) orally TID for 8 weeks. The placebo is taken on top of standard therapy for diabetes and blood pressure control.

Also known as: placebo, sugar
DR lactose pill
DR levosulpirideDRUG

Patients with non-proliferative DR will take levosulpiride (75 mg/day) orally TIDfor 8 weeks. Levosulpiride is taken on top of standard therapy for diabetes and blood pressure control.

Also known as: dopamine D2 receptor blocker
DR levosulpiride
DR vitrectomy lactose pillDRUG

Patients with proliferative DR (undergoing medically prescribed vitrectomy 7 days after starting the study medication) will have to take a lactose pill (placebo) orally TID for one week. The last placebo pill will be taken on the morning of the day vitrectomy is performed. The placebo is taken on top of standard therapy for diabetes and blood pressure control.

Also known as: placebo, sugar
DR, vitrectomy lactose pill
DR vitrectomy levosulpirideDRUG

Patients with proliferative DR (undergoing medically prescribed vitrectomy 7 days after starting the study medication) will take levosulpiride (75 mg/day) orally TID for one week. The last pill will be taken on the morning of the day vitrectomy is performed. Levosulpiride is taken on top of standard therapy for diabetes and blood pressure control.

Also known as: dopamine D2 receptor blocker
DR, vitrectomy levosulpiride
DME plus ranibizumab lactose pillDRUG

Patients with DME with conventional intravitreal antiangiogenic therapy with ranibizumab (0.5 mg every 4 weeks for 12 weeks) will take a lactose pill (placebo) orally TID for 24 weeks. The placebo is taken on top of standard therapy for diabetes and blood pressure control.

Also known as: placebo, sugar
DME plus ranibizumab lactose pill
DME plus ranibizumab levosulpirideDRUG

Patients with DME with receive intravitreal antiangiogenic therapy with ranibizumab (0.5 mg every 4 weeks for 12 weeks) will take a levosulpiride (75 mg/day) orally TID for 24 weeks. The study medication is taken on top of standard therapy for diabetes and blood pressure control.

Also known as: dopamine D2 receptor blocker
DME plus ranibizumab levosulpiride

Eligibility Criteria

Age40 Years - 69 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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)

You may not qualify if:

  • 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

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (2)

Instituto Mexicano de Oftalmologia (IMO)

Querétaro City, Querétaro, 76090, Mexico

RECRUITING

Instituto de la Retina del Bajio SC (INDEREB)

Querétaro City, Querétaro, 76187, Mexico

RECRUITING

Related Publications (11)

  • 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.

    PMID: 16043870BACKGROUND

  • 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.

    PMID: 18497878BACKGROUND

  • 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.

    PMID: 18544641BACKGROUND

  • 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.

    PMID: 20823101BACKGROUND

  • 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.

    PMID: 21913303BACKGROUND

  • 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.

    PMID: 22003113BACKGROUND

  • 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.

    PMID: 24478366BACKGROUND

  • 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.

    PMID: 25368550BACKGROUND

  • 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.

    PMID: 26568297BACKGROUND

  • 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.

    PMID: 27322457BACKGROUND

  • 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.

    PMID: 29896154BACKGROUND

Related Links

MeSH Terms

Conditions

Diabetic RetinopathyBlindnessMacular Edema

Interventions

Sugarsdimethylethylsilylimidazole

Condition Hierarchy (Ancestors)

Retinal DiseasesEye DiseasesDiabetic AngiopathiesVascular DiseasesCardiovascular DiseasesDiabetes ComplicationsDiabetes MellitusEndocrine System DiseasesVision DisordersSensation DisordersNeurologic ManifestationsNervous System DiseasesSigns and SymptomsPathological Conditions, Signs and SymptomsMacular DegenerationRetinal Degeneration

Intervention Hierarchy (Ancestors)

Carbohydrates

Study Officials

  • Carmen Clapp, Ph.D.

    Universidad Nacional Autonoma de Mexico (UNAM)

    STUDY DIRECTOR

  • Ludivina Robles Osorio, M.D., Ph.D.

    Universidad Autónoma de Querétaro

    PRINCIPAL INVESTIGATOR

  • Renata Garcia Franco, M.D.

    Instituto de la Retina del Bajio SC (INDEREB)

    PRINCIPAL INVESTIGATOR

  • Jakob Triebel, M.D.

    Institute for Clinical Chemistry, Laboratory Medicine and Transfusion Medicine, Nuremberg General Hospital

    PRINCIPAL INVESTIGATOR

  • Marlon R Garcia Roa, M.D.

    Instituto Mexicano de Oftalmología (IMO)

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Carmen Clapp, Ph.D.

CONTACT

52442 2381028clapp@unam.mx

Ludivina Robles Osorio, M.D., Ph.D.

CONTACT

52442 1921200ludirobles7@yahoo.com

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
TRIPLE
Who Masked
PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
Masking Details
Patients, care providers, and evaluators are blind to treatment allocation. This reduces the risk of bias in the measurement of outcomes, in the decision to modify or discontinue treatment, or to withdraw from trial or from analysis. The monitoring coordinator allocates the treatment.
Purpose
TREATMENT
Intervention Model
PARALLEL
Model Details: 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.
Sponsor Type
OTHER
Responsible Party
SPONSOR INVESTIGATOR
PI Title
Principal Investigator

Study Record Dates

First Submitted

May 18, 2017

First Posted

May 22, 2017

Study Start

May 24, 2017

Primary Completion (Estimated)

December 1, 2026

Study Completion (Estimated)

June 1, 2027

Last Updated

November 18, 2025

Record last verified: 2025-11

Locations

ME(2)