This study will compare the side effects of two laser treatments for diabetic macular edema,
a common condition in patients with diabetes. In macular edema, blood vessels in the
retina-a thin layer of tissue that lines the back of the eye-become leaky and the retina
swells. The macula-the center part of the retina that is responsible for fine vision-may
also swell and cause vision loss. Traditional laser treatment (argon blue or green, or
yellow) for macular swelling, or edema, causes scarring that can expand and possibly lead to
more loss of vision. A different type of laser (diode) may have less damaging effects to
the eye and fewer long-term adverse effects, but this is not known. The results of this
study on side effects of the treatments will be used to design a larger study of
effectiveness. The study will also examine whether vitamin E can reduce the damage caused
by laser treatment. Patients with elevated cholesterol levels will be invited to
participate in a cholesterol reduction part of the study to compare normal-pace cholesterol
reduction with accelerated reduction.
Patients 18 years of age and older with type 1 or type 2 diabetes and macular edema may be
eligible for this study. Candidates will be screened with the following tests and
- Medical history and physical examination.
- Eye examination to assess visual acuity (eye chart test) and eye pressure, and to
examine pupils, lens, retina and eye movements. The pupils will be dilated with drops
for this examination.
- Blood tests to measure cholesterol and vitamin E blood levels, blood clotting time,
hemoglobin A1C (a measure of diabetes control), and to evaluate liver and kidney
- Eye photography to help evaluate the status of the retina and changes that may occur in
the future. Special photographs of the inside of the eye are taken using a camera that
flashes a bright light into the eye.
- Fluorescein angiography to evaluate the eye's blood vessels. A yellow dye is injected
into an arm vein and travels to the blood vessels in the eyes. Pictures of the retina
are taken using a camera that flashes a blue light into the eye. The pictures show if
any dye has leaked from the vessels into the retina, indicating possible blood vessel
- Multifocal electroretinogram to measure electrical responses generated within the
retina. The test, which takes about 1-1/2 hours, is painless.
Participants will be randomly assigned to take 1600 IU of vitamin E or placebo (an inactive,
look-alike pill) daily. After taking the pills for 3 months or more, patients who require
laser treatment will be randomly assigned to one of the two laser therapies. (Patients with
macular edema in both eyes will receive both treatments, one in each eye.) For these
procedures, eye drops are put in the eye to numb the surface and a contact lens is placed on
the eye during the laser beam application. Several visits may be required for additional
laser treatments. The maximum number of treatments depends on how well they are working.
Patients will return for follow-up visits 1, 3, and 6 months after the first treatment, and
then every 6 months until either the patient returns for a 3-year visit; the last enrolled
patient returns for the 1-year visit; or the patient requests to leave the study. During
the follow-up visits, patients' response to treatment will be evaluated with repeat tests of
several of the screening exams.
This randomized pilot study is an important first step in planning a large multi-center
clinical trial to evaluate medical and laser approaches that could improve the visual
outcome for patients with diabetic retinopathy. This study will provide preliminary safety
and efficacy data on these therapies as well as allow for assessment of the performance of
ocular outcomes and study design for use in subsequent trials. If there are no safety
concerns, the results of this pilot will be helpful in the design of a large multicenter
clinical trial by providing data on estimates of expected treatment effects.
Using a factorial design, this study will compare (1) photocoagulation using a diode
(micropulse) laser to mild Early Treatment Diabetic Retinopathy Studt (ETDRS) style
(continuous wave laser using green or yellow wavelength) focal photocoagulation and, (2) the
effect of treating with antioxidants (high dose Vitamin E) to placebo prior to and following
laser photocoagulation. The primary outcome is a visual acuity drop or increase of 15
letters or more from baseline three year after enrollment. The secondary outcomes will be a
50% reduction in retinal thickening as measured by Optical Cohenrence Tomography (OT), a
two-step reduction in macular thickness when compared to standard stereoscopic fundus
photographs, and a 50% reduction in the area of leakage as measured by fluorescein
angiography at 1 year amd 3 years after the initial laser compared to baseline. Additional
outcomes will include the time (from baseline) of the first laser treatment and the number
of retreatments required during the course of the study. These outcomes will be assessed
for potential use in future trials. We are concerned with the following specific questions
regarding safety and efficacy:
Is the risk of visual loss in patients with clinically significant diabetic macular edema
potentially different across treatment groups?
Is there any evidence that any treatment combinations could be effective in reducing retinal
Is there any evidence that Vitamin E may affect the ability of either photocoagulation
method to reduce retinal thickening, or vice versa?
What are the estimated treatment effects on vision?
Is the number of laser treatments required to achieve a reduction in retinal thickening
similar across treatment groups?
A tertiary objective of this study will be to examine the effects of dramatically reducing
low-density lipoproteins cholesterol in patients with diabetic macular edema and elevated
serum lipids. Change in vision and change in retinal thickness will be compared across
three groups; (1) patients who do not have elevated serum lipids at baseline, (2) patients
who have elevated lipids at baseline and receive standard of care treatment, and (3)
patients who have elevated lipids at baseline and are aggressively treated
pharmacologically. This tertiary objective will be assessed for the feasibility of this
1. Patients with type 1 or 2 diabetes.
2. Patients with clinically significant macular edema in at least one eye.
3. Best corrected visual acuity 20/400 or better as measured on an ETDRS chart in the
eye(s) with clinically significant macular edema.
4. May have had proliferative diabetic retinopathy but scatter photocoagulation must be
performed more than six months ago.
5. Ocular media sufficiently clear to allow for quality fundus photography.
6. If aphakic or pseudophakic, lens removal must have occurred at least 6 months prior
7. Patient's medical status must include a likelihood of survival for 5 years.
8. Willingness to accept randomization for diet or drug therapy for lowering of elevated
9. Understand and sign the informed consent.
10. Patients over 18 years of age since the population of interest is primarily older
1. Retinopathy that requires scatter photocoagulation immediately.
2. Ocular disease other than diabetic retinopathy that may confound the outcome of the
study (e.g. age-related macular degeneration, drug toxicity, uveitis, etc.).
3. Poor likelihood of survival (of one year) due other systemic diseases (separate from
4. Poor glycemic control with hemoglobin A1C greater than 12% within one month of
5. Past or current liver disease, which precludes the use of the lipid-lowering drugs.
6. Vitamine E supplementation over and above the amount in a myltivitamin (60 IU/day)
one month prior to entry into the study.
7. History of hypersensitivity to fluorescein.
8. Prior or current macular detachment in the eligible eye(s).
9. Concurrent coumadin therapy or known bleeding diathesis.
10. Concurrent lithium therapy.
11. Concurrent treatment with a new investigational drug.
12. Malabsorption syndrome.
13. Concurrent administration of the anti-obesity drug orlistat Xenical).
14. Pregnant or lactating women.
15. Chronic requirement for any ocular medication for diseases that in the judgement of
the examining physician, are vision threatening or may affect the primary outcome.
16. Current history of malignancy (except participants having a basal cell carcinoma that
was treated successfully, or other malignancy operated on and in remission for 5
years prior to inclusion in the trial).
17. Participants whose diabetic macular edema, in the opinion of the Principal
Investigator, cannot benefit from laser treatments, including those with subretinal
fibrosis, severe macular non-perfusion, or parafoveal leakage in both eyes.
18. Participants that have a history of focal laser treatment, and are thought to be
refractory to laser treatment or were treated within 3 months of baseline. (a
minimal number of previous laser treatments are acceptable at the discretion of the
19. Participants with clear vitreal-retinal traction in both eyes.
20. Participants requiring therapy with topical prostaglandin analogues.