Effect of Levosulpiride on Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema

NCT ID: NCT03161652

Last Updated: 2025-11-18

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

120 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-05-24

Study Completion Date

2027-06-30

Brief Summary

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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

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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.

Conditions

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Diabetic Macular Edema Diabetic Retinopathy

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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 Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Outcome Assessors
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.

Study Groups

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DME lactose pill

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

Group Type PLACEBO_COMPARATOR

DME lactose pill

Intervention Type DRUG

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.

DME levosulpiride

Patients with DME will be randomized to take levosulpiride.

Group Type EXPERIMENTAL

DME levosulpiride

Intervention Type DRUG

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.

DR lactose pill

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

Group Type PLACEBO_COMPARATOR

DR lactose pill

Intervention Type DRUG

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.

DR levosulpiride

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

Group Type EXPERIMENTAL

DR levosulpiride

Intervention Type DRUG

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.

DR, vitrectomy lactose pill

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

Group Type PLACEBO_COMPARATOR

DR vitrectomy lactose pill

Intervention Type DRUG

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.

DR, vitrectomy levosulpiride

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

Group Type EXPERIMENTAL

DR vitrectomy levosulpiride

Intervention Type DRUG

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.

DME plus ranibizumab lactose pill

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

Group Type PLACEBO_COMPARATOR

DME plus ranibizumab lactose pill

Intervention Type DRUG

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.

DME plus ranibizumab levosulpiride

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

Group Type EXPERIMENTAL

DME plus ranibizumab levosulpiride

Intervention Type DRUG

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.

Interventions

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DME lactose pill

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.

Intervention Type DRUG

DME levosulpiride

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.

Intervention Type DRUG

DR lactose pill

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.

Intervention Type DRUG

DR levosulpiride

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.

Intervention Type DRUG

DR vitrectomy lactose pill

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.

Intervention Type DRUG

DR vitrectomy levosulpiride

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.

Intervention Type DRUG

DME plus ranibizumab lactose pill

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.

Intervention Type DRUG

DME plus ranibizumab levosulpiride

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.

Intervention Type DRUG

Other Intervention Names

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placebo, sugar dopamine D2 receptor blocker placebo, sugar dopamine D2 receptor blocker placebo, sugar dopamine D2 receptor blocker placebo, sugar dopamine D2 receptor blocker

Eligibility Criteria

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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)

* 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
Minimum Eligible Age

40 Years

Maximum Eligible Age

69 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Instituto Mexicano de Oftalmologia (IMO)

UNKNOWN

Sponsor Role collaborator

Universidad Autónoma de Querétaro

OTHER

Sponsor Role collaborator

General Hospital Nuremberg & Paracelsus Medical University Nuremberg

UNKNOWN

Sponsor Role collaborator

Instituto de la Retina del Bajio SC (INDEREB)

UNKNOWN

Sponsor Role collaborator

Instituto de Neurobiología, Universidad Nacional Autonoma de Mexico (UNAM)

UNKNOWN

Sponsor Role collaborator

Carmen Clapp

OTHER

Sponsor Role lead

Responsible Party

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Carmen Clapp

Principal Investigator

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Carmen Clapp, Ph.D.

Role: STUDY_DIRECTOR

Universidad Nacional Autonoma de Mexico (UNAM)

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

Role: PRINCIPAL_INVESTIGATOR

Universidad Autónoma de Querétaro

Renata Garcia Franco, M.D.

Role: PRINCIPAL_INVESTIGATOR

Instituto de la Retina del Bajio SC (INDEREB)

Jakob Triebel, M.D.

Role: PRINCIPAL_INVESTIGATOR

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

Marlon R Garcia Roa, M.D.

Role: PRINCIPAL_INVESTIGATOR

Instituto Mexicano de Oftalmología (IMO)

Locations

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Instituto Mexicano de Oftalmologia (IMO)

Querétaro City, Querétaro, Mexico

Site Status RECRUITING

Instituto de la Retina del Bajio SC (INDEREB)

Querétaro City, Querétaro, Mexico

Site Status RECRUITING

Countries

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Mexico

Central Contacts

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Carmen Clapp, Ph.D.

Role: CONTACT

52442 2381028

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

Role: CONTACT

52442 1921200 ext. 5301

Facility Contacts

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Ellery Lopez Star, M.D.

Role: primary

52442 229 0776 ext. 118

Marlon R García Roa, M.D.

Role: backup

52442 229 0776

Renata Garcia Franco, M.D.

Role: primary

52442 3407952

Carlos D Nuñez Amaro, M.Sc.

Role: backup

52442 3961722

References

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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.

Reference Type BACKGROUND
PMID: 16043870 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 18497878 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 18544641 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 20823101 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 21913303 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 22003113 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 24478366 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25368550 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 26568297 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 27322457 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 29896154 (View on PubMed)

Related Links

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http://personal.inb.unam.mx/clapp/

Carmen Clapp's research web page

http://www.inb.unam.mx/

Instituto de Neurobiologia, Universidad Nacional Autonoma de Mexico web page

https://imoiap.com.mx/

Instituto Mexicano de Oftalmologia web page

Other Identifiers

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LDRDME_247164

Identifier Type: -

Identifier Source: org_study_id

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