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

Sponsor

University of Guadalajara (Other)

Overall Status

Completed

CT.gov ID

NCT03702374

Collaborator

Instituto Mexicano del Seguro Social (Other)

132

Enrollment

Location

Arms

27.2

Actual Duration (Months)

4.9

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

132 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 :

Sep 26, 2018

Actual Primary Completion Date :

Nov 30, 2020

Actual Study Completion Date :

Dec 31, 2020

Arms and Interventions

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 Names: 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 Names: Magnesia

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 Names:

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 Names:

Magnesia

Outcome Measures

Primary Outcome Measures

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

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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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