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

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ClinicalTrials.gov Identifier: NCT03161652
Recruitment Status : Recruiting
First Posted : May 22, 2017
Last Update Posted : June 9, 2020
Sponsor:
Collaborators:
Instituto Mexicano de Oftalmologia (IMO)
Universidad Autónoma de Querétaro
General Hospital Nuremberg & Paracelsus Medical University Nuremberg
Instituto de la Retina del Bajio SC (INDEREB)
Instituto de Neurobiología, Universidad Nacional Autonoma de Mexico (UNAM)
Information provided by (Responsible Party):
Carmen Clapp, Universidad Nacional Autonoma de Mexico

Tracking Information
First Submitted Date  ICMJE May 18, 2017
First Posted Date  ICMJE May 22, 2017
Last Update Posted Date June 9, 2020
Actual Study Start Date  ICMJE May 24, 2017
Estimated Primary Completion Date May 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 18, 2017)
  • 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)
  • 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).
  • 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
  • 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.
  • 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
  • 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
  • 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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 18, 2017)
  • 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)
  • 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.
  • Blood pressure [ Time Frame: 5 minutes ]
    Systolic and diastolic values in mmHg
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Levosulpiride on Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema
Official Title  ICMJE Clinical Trial to Evaluate the Safety and Efficacy of Levosulpiride to Improve Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Masking Description:
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.
Primary Purpose: Treatment
Condition  ICMJE
  • Diabetic Macular Edema
  • Diabetic Retinopathy
Intervention  ICMJE
  • 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 Name: placebo, sugar
  • 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 Name: dopamine D2 receptor blocker
  • 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 Name: placebo, sugar
  • 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 Name: dopamine D2 receptor blocker
  • 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 Name: placebo, sugar
  • 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 Name: dopamine D2 receptor blocker
  • 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 Name: placebo, sugar
  • 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 Name: dopamine D2 receptor blocker
Study Arms  ICMJE
  • Placebo Comparator: DME lactose pill
    Patients with DME will be randomized to take a lactose pill (placebo).
    Intervention: Drug: DME lactose pill
  • Experimental: DME levosulpiride
    Patients with DME will be randomized to take levosulpiride.
    Intervention: Drug: DME levosulpiride
  • Placebo Comparator: DR lactose pill
    Patients with non-proliferative DR will be randomized to take a lactose pill (placebo)
    Intervention: Drug: DR lactose pill
  • Experimental: DR levosulpiride
    Patients with non-proliferative DR will be randomized to take levosulpiride
    Intervention: Drug: DR levosulpiride
  • 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).
    Intervention: Drug: DR vitrectomy lactose pill
  • Experimental: DR, vitrectomy levosulpiride
    Patients with proliferative DR (undergoing medically prescribed vitrectomy 7 days after starting the study) will be randomized to take levosulpiride.
    Intervention: Drug: DR vitrectomy levosulpiride
  • 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)
    Intervention: Drug: DME plus ranibizumab lactose pill
  • Experimental: DME plus ranibizumab levosulpiride
    Patients with DME that will receive intravitreal antiangiogenic therapy with ranibizumab will be randomized to take levosulpiride
    Intervention: Drug: DME plus ranibizumab levosulpiride
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 3, 2017)
120
Original Estimated Enrollment  ICMJE
 (submitted: May 18, 2017)
136
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date May 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 69 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Carmen Clapp, Ph.D. 52442 2381028 clapp@unam.mx
Contact: Ludivina Robles Osorio, M.D., Ph.D. 52442 1921200 ext 5301 ludirobles7@yahoo.com
Listed Location Countries  ICMJE Mexico
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03161652
Other Study ID Numbers  ICMJE LDRDME_247164
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
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.
Responsible Party Carmen Clapp, Universidad Nacional Autonoma de Mexico
Study Sponsor  ICMJE Carmen Clapp
Collaborators  ICMJE
  • Instituto Mexicano de Oftalmologia (IMO)
  • Universidad Autónoma de Querétaro
  • 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  ICMJE
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 Oftalmología (IMO)
PRS Account Universidad Nacional Autonoma de Mexico
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP