Clinical trial NCT03702374: Combined Antioxidant Therapy on Oxidative Stress, Mitochondrial Dysfunction Markers in Diabetic Retinopathy
Official title: Effect of Prolonged Combined Antioxidant Therapy Intake on Oxidative Stress and Mitochondrial Dysfunction Markers in Patients With Diabetic Retinopathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetic Retinopathy
Keywords: diabetic retinopathy
oxidative stress
mitochondrial dysfunction
oxidative markers
diabetes
antioxidant therapy
Lead sponsor: University of Guadalajara
Sponsor class: OTHER
Collaborators: name: Instituto Mexicano del Seguro Social
First posted: 2018-10-11
Enrollment: 132
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Changes in concentration of serum malondialdehyde after intervention.
timeFrame: 3 measures will be made, 1 at baseline, another one after 6 months and a last one after completion of 12 months of intervention.
measure: Changes in ATPase activity after intervention from baseline
timeFrame: 3 measures will be made, 1 at baseline, another one after 6 months and a last one after 12 months of intervention
measure: Changes in concentration of total antioxidant capacity (TAC) after intervention from baseline.
timeFrame: 3 measures will be made, 1 at baseline, another one after 6 months and a last one after 12 months of intervention
Secondary outcomes:
measure: Diabetic retinopathy severity progress at the end of intervention from baseline
timeFrame: 2 measures will be made, 1 at baseline and a second one after 12 months of intervention.
Other outcomes:
Locations:
city: Guadalajara
country: Mexico
facility: Institute of Experimental and Clinical Therapeutics,
state: Jalisco
Study officials:
affiliation: Clinical Investigator at University of Guadalajara
name: Adolfo D. Rodriguez-Carrizalez, PhD
role: STUDY_DIRECTOR
References:
citation: Rodriguez-Carrizalez AD, Castellanos-Gonzalez JA, Martinez-Romero EC, Miller-Arrevillaga G, Villa-Hernandez D, Hernandez-Godinez PP, Ortiz GG, Pacheco-Moises FP, Cardona-Munoz EG, Miranda-Diaz 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.
citation: Rodriguez-Carrizalez AD, Castellanos-Gonzalez JA, Martinez-Romero EC, Miller-Arrevillaga G, Roman-Pintos LM, Pacheco-Moises FP, Miranda-Diaz 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.
citation: Rodriguez-Carrizalez AD, Castellanos-Gonzalez JA, Martinez-Romero EC, Miller-Arrevillaga G, Pacheco-Moises FP, Roman-Pintos LM, Miranda-Diaz 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.
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
citation: Lopez-Contreras AK, Martinez-Ruiz MG, Olvera-Montano C, Robles-Rivera RR, Arevalo-Simental DE, Castellanos-Gonzalez JA, Hernandez-Chavez A, Huerta-Olvera SG, Cardona-Munoz EG, Rodriguez-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):891. doi: 10.3390/antiox9090891.
citation: Robles-Rivera RR, Castellanos-Gonzalez JA, Olvera-Montano C, Flores-Martin RA, Lopez-Contreras AK, Arevalo-Simental DE, Cardona-Munoz EG, Roman-Pintos LM, Rodriguez-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.
citation: Cecilia OM, Jose Alberto CG, Jose NP, Ernesto German CM, Ana Karen LC, Luis Miguel RP, Ricardo Raul 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.