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Combined Antioxidant Therapy on Oxidative Stress, Mitochondrial Dysfunction Markers in Diabetic Retinopathy

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ClinicalTrials.gov Identifier: NCT03702374
Recruitment Status : Recruiting
First Posted : October 11, 2018
Last Update Posted : October 29, 2018
Sponsor:
Collaborator:
Instituto Mexicano del Seguro Social
Information provided by (Responsible Party):
Adolfo Daniel Rodriguez-Carrizalez, University of Guadalajara

Brief Summary:

The present study aims to support previous research on antioxidant therapy effects in diabetic retinopathy outcome. The investigators intend to assess 180 patients with diabetic retinopathy in different stages (moderate, severe and proliferative), whom either will be assigned to placebo group or combined antioxidant therapy. Each group will receive the intervention for 12 months. Such intervention consists in taking one tablet (placebo or antioxidant therapy) orally, a day.

At baseline, blood and urine samples will be collected in order to assess metabolic and oxidative stress status, mitochondrial function or dysfunction, liver and kidney function. In addition, fluorescein angiography will be done for the categorization of diabetic retinopathy. After six months and at the end of the intervention, blood and urine measurements as well as angiographies will be done for comparing the outcomes between both groups and correlate oxidative stress status, mitochondrial dysfunction with grade of retinopathy.


Condition or disease Intervention/treatment Phase
Diabetic Retinopathy Drug: Combined antioxidant therapy Other: Placebo Phase 3

Detailed Description:

Diabetic retinopathy is a diabetes microvascular complication due to an insufficient oxygen supply to its endothelial cells in states of constant hyperglycemia. This entity is classified in two main categories: non-proliferative diabetic retinopathy and proliferative diabetic retinopathy, the latter is characterized for the presence of neovascularization as oppose to the first one.

Oxidative stress has been considered as one of the main factors in the development of diabetic retinopathy. It results from an imbalance between oxidants production and cellular antioxidant defenses, which provokes DNA damage in the mitochondrion altering its capacity to produce ATP (Adenosine Triphosphate) resulting in what is known as mitochondrial dysfunction.

Diabetic retinopathy management merely comprises glycemic, lipemic and blood pressure control. Secondary intervention includes anti-platelet agents, protein-kinase C inhibitors, aldolase reductase inhibitors, laser and vitrectomy. Antioxidant therapy has been used as a co-adjuvant for these interventions, as antioxidant substances that complement action and efficacy of the established treatment for diabetic retinopathy.

Diabetic retinopathy is the principal cause of blindness in persons between 20 and 70 years of age. Its prevalence is, approximately, 25% 5 years after diagnosis.

Which is why the investigators intend to prove if the antioxidant therapy is able to change retinopathy outcomes in oxidative stress, mitochondrial dysfunction and/or grade of retinopathy.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effect of Prolonged Combined Antioxidant Therapy Intake on Oxidative Stress and Mitochondrial Dysfunction Markers in Patients With Diabetic Retinopathy
Actual Study Start Date : September 26, 2018
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : November 1, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Combined Antioxidant Therapy group
This arm will be administered with the combined antioxidant therapy, and will consist of 30 patients with moderate non-proliferative diabetic retinopathy (NPDR), 30 subjects with severe NPDR and 30 patients with Proliferative diabetic retinopathy.
Drug: Combined antioxidant therapy
It consists in a tablet with lutein (10 mg), astaxanthin (4 mg), Zeaxanthin (1mg), vitamin C (L-ascorbic acid 180mg), vitamin E (DL-alpha tocopherol 30mg), zinc (zinc oxide 20mg), copper (copper sulfate 1mg), taken once a day for 12 months
Other Name: Drusen Laz

Placebo Comparator: Placebo group
This arm will be administered with placebo, and will consist of 30 patients with moderate non-proliferative diabetic retinopathy (NPDR), 30 subjects with severe NPDR and 30 patients with Proliferative diabetic retinopathy.
Other: Placebo
It consists in a capsule with 100mg of magnesium oxide.
Other Name: Magnesia




Primary Outcome Measures :
  1. Changes in concentration of serum malondialdehyde after intervention. [ Time Frame: 3 measures will be made, 1 at baseline, another one after 6 months and a last one after completion of 12 months of intervention. ]
    The investigators will consider changes presented in plasma concentrations of malondialdehyde from baseline to the end of the intervention. The investigators expect to find a decrease in malondialdehyde concentrations in the supplemented group.

  2. Changes in ATPase activity after intervention from baseline [ Time Frame: 3 measures will be made, 1 at baseline, another one after 6 months and a last one after 12 months of intervention ]
    The investigators will consider changes showed in ATPase activity after the intervention compared to baseline. The investigators expect to find a decrease in ATPase activity in the supplemented group.

  3. Changes in concentration of total antioxidant capacity (TAC) after intervention from baseline. [ Time Frame: 3 measures will be made, 1 at baseline, another one after 6 months and a last one after 12 months of intervention ]
    The investigators will consider changes presented in plasma concentrations of total antioxidant capacity (TAC) from baseline to the end of the intervention. The investigators expect to find TAC augmentation in the supplemented group.


Secondary Outcome Measures :
  1. Diabetic retinopathy severity progress at the end of intervention from baseline [ Time Frame: 2 measures will be made, 1 at baseline and a second one after 12 months of intervention. ]

    Change in grade of retinopathy according to the International Clinical Diabetic Retinopathy Disease Severity Scale.

    No apparent retinopathy: No abnormalities. Mild non-proliferative diabetic retinopathy: presence of microaneurysms only. Moderate non-proliferaitve diabetic retinopathy: More than just microaneurysms but less than Severe Non-proliferative diabetic retinopathy.

    Severe non-proliferative diabetic retinopathy: Presence of more than 20 intraretinal hemorrhages in each of 4 quadrants, venous beading in 2 or more quadrants, prominent intraretinal microvascular anormalities in one or more quadrants, no signs of proliferative retinopathy.

    Proliferative diabetic retinopathy: presence of neovascularization, or vitreous/preretinal hemorrhage.

    Note: Progression from a moderate non-proliferative diabetic retinopathy to a severe non-proliferative diabetic retinopathy, and from either of those two to proliferative retinopathy will be considered as a worse outcome.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Patients with type 2 diabetes with moderate or severe non-proliferative diabetic retinopathy without clinically significant macular edema.
  • Patients with type 2 diabetes with proliferative diabetic retinopathy without clinically significant macular edema.
  • In current treatment that may include: metformin, glibenclamide, pravastatin, bezafibrate, losartan, nifedipine or captopril.
  • HbA1c equal or lower than 9%
  • LDL under 190mg/dl, triglycerides under 500mg/dl)
  • Blood pressure under 180/110 mmHg
  • Non-smoker or inactive for at least 6 months
  • Signed informed consent

Exclusion Criteria:

  • Antioxidant therapy intake over the last 6 months. Antioxidant dietary intake that surpasses the daily DIR (dietary intake recommendations)
  • Patients who require secondary intervention (laser surgery)
  • Patients with previous history of myocardial infarction, ictus or severe peripheral vasculopathy
  • Patients with pathologies that increase oxidative stress
  • Patients with neurodegenerative or carcinogen processes
  • Hepatic or renal failure
  • Pregnancy
  • Patients with hypersensitivity to therapy components
  • Other ocular pathologies, such as cataract, glaucoma, corneal dystrophy, macular degeneration among others
  • Patients who are currently participating in other clinical trials

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03702374


Contacts
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Contact: Adolfo D. Rodríguez-Carrizalez, PhD 10585200 ext 33658 adolfo.rodriguez@academicos.udg.mx
Contact: Cecilia Olvera-Montaño, MD 10585200 ext 33658 ceciliaom.drcrt@gmail.com

Locations
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Mexico
Institute of Experimental and Clinical Therapeutics, Recruiting
Guadalajara, Jalisco, Mexico, 44340
Contact: Adolfo D. Rodriguez-Carrizalez, PhD    +52 33 10585200 ext 33658    adolfo.rodriguez@academicos.udg.mx   
Contact: Cecilia Olvera-Montaño, MD    +52 33 10 58 52 00 ext 33658    ceciliaom.drcrt@gmail.com   
Sub-Investigator: Cecilia Olvera-Montaño, MD         
Sub-Investigator: José A. Castellanos-González, MSc         
Sub-Investigator: Alejandra G Miranda-Díaz, PhD         
Sponsors and Collaborators
University of Guadalajara
Instituto Mexicano del Seguro Social
Investigators
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Study Director: Adolfo D. Rodriguez-Carrizalez, PhD Clinical Investigator at University of Guadalajara

Publications:
Sonia Sifuentes-Franco, Adolfo Daniel Rodríguez-Carrizalez, Sandra Carrillo- Ibarra, José Alberto Castellanos-González, Esaú César Martínez-Romero, Guillermo Miller-Arrevillaga and Alejandra Guillermina Miranda-Díaz. The effect of Ubiquinone administration on oxidative DNA damage and repair in plasma levels in non-proliferative diabetic retinopathy.Diabetes Management 2017;7(2):186-191

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Responsible Party: Adolfo Daniel Rodriguez-Carrizalez, Clinical Professor, University of Guadalajara
ClinicalTrials.gov Identifier: NCT03702374     History of Changes
Other Study ID Numbers: RD-20170102
First Posted: October 11, 2018    Key Record Dates
Last Update Posted: October 29, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: The results of this study will be published in an open access journal with impact factor according to Journal Citation Reports. Considering the global clinical status of participants before and after of pharmacological intervention.

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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

Keywords provided by Adolfo Daniel Rodriguez-Carrizalez, University of Guadalajara:
diabetic retinopathy
oxidative stress
mitochondrial dysfunction
oxidative markers
diabetes
antioxidant therapy

Additional relevant MeSH terms:
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Retinal Diseases
Diabetic Retinopathy
Eye Diseases
Diabetic Angiopathies
Vascular Diseases
Cardiovascular Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs