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

Diabetic Retinopathy Clinical Trial

Official title:

Effect of Prolonged Combined Antioxidant Therapy Intake on Oxidative Stress and Mitochondrial Dysfunction Markers in Patients With Diabetic Retinopathy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03702374
• Other study ID #: RD-20170102
• Status: Completed
• Phase: Phase 3
• Start date: September 26, 2018
• Est. completion date: December 31, 2020

Study information

• Verified date: March 2022
• Source: University of Guadalajara
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 132
• Est. completion date: December 31, 2020
• Est. primary completion date: November 30, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetic Retinopathy
• Retinal Diseases

Intervention

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:
• Placebo
It consists in a capsule with 100mg of magnesium oxide.

Locations

Country	Name	City	State
Mexico	Institute of Experimental and Clinical Therapeutics,	Guadalajara	Jalisco

Sponsors (2)

Lead Sponsor	Collaborator
University of Guadalajara	Instituto Mexicano del Seguro Social

Country where clinical trial is conducted

Mexico, 

References & Publications (7)

Cecilia OM, José Alberto CG, José NP, Ernesto Germán CM, Ana Karen LC, Luis Miguel RP, Ricardo Raúl RR, Adolfo Daniel RC. Oxidative Stress as the Main Target in Diabetic Retinopathy Pathophysiology. J Diabetes Res. 2019 Aug 14;2019:8562408. doi: 10.1155/2019/8562408. eCollection 2019. Review. — View Citation

López-Contreras AK, Martínez-Ruiz MG, Olvera-Montaño C, Robles-Rivera RR, Arévalo-Simental DE, Castellanos-González JA, Hernández-Chávez A, Huerta-Olvera SG, Cardona-Muñoz EG, Rodríguez-Carrizalez AD. Importance of the Use of Oxidative Stress Biomarkers and Inflammatory Profile in Aqueous and Vitreous Humor in Diabetic Retinopathy. Antioxidants (Basel). 2020 Sep 20;9(9). pii: E891. doi: 10.3390/antiox9090891. Review. — View Citation

Robles-Rivera RR, Castellanos-González JA, Olvera-Montaño C, Flores-Martin RA, López-Contreras AK, Arevalo-Simental DE, Cardona-Muñoz EG, Roman-Pintos LM, Rodríguez-Carrizalez AD. Adjuvant Therapies in Diabetic Retinopathy as an Early Approach to Delay Its Progression: The Importance of Oxidative Stress and Inflammation. Oxid Med Cell Longev. 2020 Mar 11;2020:3096470. doi: 10.1155/2020/3096470. eCollection 2020. Review. — View Citation

Rodríguez-Carrizalez AD, Castellanos-González JA, Martínez-Romero EC, Miller-Arrevillaga G, Pacheco-Moisés FP, Román-Pintos LM, Miranda-Díaz AG. The effect of ubiquinone and combined antioxidant therapy on oxidative stress markers in non-proliferative diabetic retinopathy: A phase IIa, randomized, double-blind, and placebo-controlled study. Redox Rep. 2016 Jul;21(4):155-63. doi: 10.1179/1351000215Y.0000000040. Epub 2015 Aug 31. — View Citation

Rodríguez-Carrizalez AD, Castellanos-González JA, Martínez-Romero EC, Miller-Arrevillaga G, Román-Pintos LM, Pacheco-Moisés FP, Miranda-Díaz AG. The antioxidant effect of ubiquinone and combined therapy on mitochondrial function in blood cells in non-proliferative diabetic retinopathy: A randomized, double-blind, phase IIa, placebo-controlled study. Redox Rep. 2016 Jul;21(4):190-5. doi: 10.1179/1351000215Y.0000000032. Epub 2016 Feb 5. — View Citation

Rodríguez-Carrizalez AD, Castellanos-González JA, Martínez-Romero EC, Miller-Arrevillaga G, Villa-Hernández D, Hernández-Godínez PP, Ortiz GG, Pacheco-Moisés FP, Cardona-Muñoz EG, Miranda-Díaz AG. Oxidants, antioxidants and mitochondrial function in non-proliferative diabetic retinopathy. J Diabetes. 2014 Mar;6(2):167-75. doi: 10.1111/1753-0407.12076. Epub 2013 Aug 21. — View Citation

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in concentration of serum malondialdehyde after 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.	3 measures will be made, 1 at baseline, another one after 6 months and a last one after completion of 12 months of intervention.
Primary	Changes in ATPase activity after intervention from baseline	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 measures will be made, 1 at baseline, another one after 6 months and a last one after 12 months of intervention
Primary	Changes in concentration of total antioxidant capacity (TAC) after intervention from baseline.	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.	3 measures will be made, 1 at baseline, another one after 6 months and a last one after 12 months of intervention
Secondary	Diabetic retinopathy severity progress at the end of intervention from baseline	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.	2 measures will be made, 1 at baseline and a second one after 12 months of intervention.