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

Official title

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

Overview

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.

Interventions

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Primary outcome measures

• Visual acuity [Time frame: 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 hard exudates and hemorrhages [Time frame: 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.]
• Prolactin serum levels [Time frame: 1-2 minutes (duration of blood withdrawal)]
• Prolactin vitreous levels [Time frame: 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)]

Secondary outcome measures (3)

• Pyruvic glutamic transaminase (TGP) and thyroid stimulating hormone (TSH) serum levels [Time frame: 1-2 minutes (duration of blood withdrawal)]
• Blood glycated hemoglobin and creatinine serum levels [Time frame: 1-2 minutes (duration of blood withdrawal)]
• Blood pressure [Time frame: 5 minutes]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Mexico · 2 centers

• Instituto Mexicano de Oftalmologia (IMO) — Querétaro City
• Instituto de la Retina del Bajio SC (INDEREB) — Querétaro City

Publications

• 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 16043870
• 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 18497878
• 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 18544641
• 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 20823101
• 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 21913303
• 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 22003113
• 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 24478366
• 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 25368550

Identifiers

NCT: NCT03161652 · LDRDME_247164

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗