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

August 23, 2023 updated by: Carmen Clapp

Clinical Trial to Evaluate the Safety and Efficacy of Levosulpiride to Improve Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema.

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

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

120

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Carmen Clapp, Ph.D.
  • Phone Number: 52442 2381028
  • Email: clapp@unam.mx

Study Contact Backup

  • Name: Ludivina Robles Osorio, M.D., Ph.D.
  • Phone Number: 5301 52442 1921200
  • Email: ludirobles7@yahoo.com

Study Locations

  • Mexico
      • Queretaro, Mexico, 76090
        • Recruiting
        • Instituto Mexicano de Oftalmologia (IMO)
        • Contact:
        • Contact:
        • Principal Investigator:
          • Marlon R Garcia Roa, M.D.
        • Sub-Investigator:
          • Yolanda Villalpando Gomez, M.D.
        • Sub-Investigator:
          • Carlos D Nuñez Amaro, B.Sc.
    • Queretaro
      • Querétaro City, Queretaro, Mexico, 76187
        • Recruiting
        • Instituto de la Retina del Bajio SC (INDEREB)
        • Contact:
        • Contact:
        • Principal Investigator:
          • Renata Garcia Franco, M.D.
        • Sub-Investigator:
          • Carlos Nuñez Amaro, M.Sc.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years to 69 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: DME lactose pill
Patients with DME will be randomized to take a lactose pill (placebo).
Drug: 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.
Other Names:
  • placebo, sugar
Experimental: DME levosulpiride
Patients with DME will be randomized to take levosulpiride.
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.
Other Names:
  • dopamine D2 receptor blocker
Placebo Comparator: DR lactose pill
Patients with non-proliferative DR will be randomized to take a lactose pill (placebo)
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.
Other Names:
  • placebo, sugar
Experimental: DR levosulpiride
Patients with non-proliferative DR will be randomized to take levosulpiride
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.
Other Names:
  • dopamine D2 receptor blocker
Placebo Comparator: 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).
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.
Other Names:
  • placebo, sugar
Experimental: DR, vitrectomy levosulpiride
Patients with proliferative DR (undergoing medically prescribed vitrectomy 7 days after starting the study) will be randomized to take levosulpiride.
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.
Other Names:
  • dopamine D2 receptor blocker
Placebo Comparator: 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)
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.
Other Names:
  • placebo, sugar
Experimental: DME plus ranibizumab levosulpiride
Patients with DME that will receive intravitreal antiangiogenic therapy with ranibizumab will be randomized to take levosulpiride
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.
Other Names:
  • dopamine D2 receptor blocker

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Visual acuity
Time Frame: 5 minutes
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
Time Frame: Pupils are dilated (eye drops) for 10 to 15 minutes and optical coherence tomography (OCT) images recorded during 5 minutes.
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
Time Frame: Pupils are dilated (eye drops) for 10 to 15 minutes and fundus images recorded during 5 minutes
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
Time Frame: 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.
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
Time Frame: 1-2 minutes (duration of blood withdrawal)
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
Time Frame: 2 minutes (duration of vitreous withdrawal during medically prescribed vitrectomy)
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
Time Frame: 2 minutes (duration of vitreous withdrawal during medically prescribed vitrectomy)
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pyruvic glutamic transaminase (TGP) and thyroid stimulating hormone (TSH) serum levels
Time Frame: 1-2 minutes (duration of blood withdrawal)
U/L (TGP) and uU/mL (TSH) quantified in serum samples by the Bioclin Kinetic Transaminase ALT (TGP) Kit and the automatic quimioluminescent evaluator (TSH)
1-2 minutes (duration of blood withdrawal)
Blood glycated hemoglobin and creatinine serum levels
Time Frame: 1-2 minutes (duration of blood withdrawal)
Glycated hemoglobin (evaluated by boronate affinity chromatography) and creatinine (evaluated by the Jaffe reaction) levels are expressed as % and mg/dL, respectively.
1-2 minutes (duration of blood withdrawal)
Blood pressure
Time Frame: 5 minutes
Systolic and diastolic values in mmHg
5 minutes

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Carmen Clapp

Collaborators

Universidad Autónoma de Querétaro
Instituto Mexicano de Oftalmologia (IMO)
General Hospital Nuremberg & Paracelsus Medical University Nuremberg
Instituto de la Retina del Bajio SC (INDEREB)
Instituto de Neurobiología, Universidad Nacional Autonoma de Mexico (UNAM)

Investigators

  • Study Director: Carmen Clapp, Ph.D., Universidad Nacional Autonoma de Mexico (UNAM)
  • Principal Investigator: 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 Oftalmologia (IMO)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 24, 2017

Primary Completion (Estimated)

June 1, 2025

Study Completion (Estimated)

June 1, 2025

Study Registration Dates

First Submitted

May 18, 2017

First Submitted That Met QC Criteria

May 18, 2017

First Posted (Actual)

May 22, 2017

Study Record Updates

Last Update Posted (Actual)

August 25, 2023

Last Update Submitted That Met QC Criteria

August 23, 2023

Last Verified

August 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • LDRDME_247164

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

It is yet undecided whether case reports will be published in medical journals throughout the course of the study. No identifier linking participants in the study to research records will be made public or reported.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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