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

Phase 3

Completed

• Conditions: Diabetic Retinopathy
• Interventions: Drug: Combined antioxidant therapy; Other: Placebo

• Registration Number: NCT03702374
• Lead Sponsor: 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.

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.

Study Timeline

• Study Start: 2018-09-26
• Study First Submitted: 2018-10-02
• Study First Submitted QC: 2018-10-09
• Study First Posted: 2018-10-11
• Primary Completion: 2020-11-30
• Study Completion: 2020-12-31
• Status Verified: 2022-03
• Last Update Submitted: 2022-03-21
• Last Update Posted: 2022-04-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 132

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Combined Antioxidant Therapy group	Combined antioxidant therapy	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.
Placebo group	Placebo	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.

Primary Outcome Measures

Name	Time	Method
Changes in concentration of serum malondialdehyde after intervention.	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.
Changes in ATPase activity after intervention from baseline	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.
Changes in concentration of total antioxidant capacity (TAC) after intervention from baseline.	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

Name	Time	Method
Diabetic retinopathy severity progress at the end of intervention from baseline	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.

Trial Locations

Locations (1)

Institute of Experimental and Clinical Therapeutics,; 🇲🇽 Guadalajara, Jalisco, Mexico