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

Study Overview
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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.

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

Conditions
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Diabetic Macular Edema, Diabetic Retinopathy

Intervention / Treatment
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* Drug: DME lactose pill
* Drug: DME levosulpiride
* Drug: DR lactose pill
* Drug: DR levosulpiride
* Drug: DR vitrectomy lactose pill
* Drug: DR vitrectomy levosulpiride
* Drug: DME plus ranibizumab lactose pill
* Drug: DME plus ranibizumab levosulpiride


Participation Criteria
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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) 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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pyruvic glutamic transaminase (TGP) and thyroid stimulating hormone (TSH) serum levels | 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 | 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 | Systolic and diastolic values in mmHg | 5 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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eye, diabetic retinopathy, blindness, macular edema, prolactin, dopamine antagonists, peptide hormones