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. Studies with a different type of laser (diode) have shown no adverse
effects to the retina, but long-term effects of this treatment are not known. The results of
this study on side effects of the treatments will be used to design a larger study of
effectiveness. This study will also examine whether vitamin E can reduce the damage caused
by laser treatment. Patients with diabetic eye disease who take vitamin E have increased
blood flow through the vessels of the retina, as well as improved kidney function. 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 - to review past medical conditions and treatments.
- Physical examination - to measure vital signs (pulse, blood pressure, temperature,
breathing rate) and examine the head and neck, heart, lungs, abdomen, arms and legs.
- Eye examination - to assess visual acuity (eye chart test) and 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
- 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. From 2 to 20 pictures may be taken, depending on
the eye condition.
- 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
Participants will be randomly assigned to receive one of the two laser treatments. They will
also be randomly assigned to take 1600 IU of vitamin E or placebo (an inactive, look-alike
pill) daily. For the laser treatment, 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 the treatment is working.
On their first visit, patients will be given vitamin C. After taking the vitamin for 1
month, they will return to the clinic for the first laser treatment. They will followed 1,
3, 6, 9, and 12 months after the first treatment, and then every 6 months until either 1)
the patient returns for a 3-year visit; 2) the last enrolled patient returns for the 1-year
visit, or the patient requests to leave the study. During these visits, several of the exams
described above will be repeated to evaluate the response to treatment and check for side
effects of the vitamin E.
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
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. A larger trial will
proceed regardless of whether or not this study identifies statistically significant main
Using a partial factorial design, this study will compare (1) diode (micropulse) laser
photocoagulation to mild ETDRS style focal photocoagulation and, (2) treatment with Vitamin
E, a COX-2 inhibitor (celecoxib), or placebo prior to and following laser photocoagulation.
The primary safety outcome is a visual acuity drop of 15 letters or more from baseline one
year following initial laser treatment. The primary efficacy outcome will be reduction of
the retinal thickening defined as an improvement by at least two steps (on standard fundus
photos) combined with a 50% reduction in the area of fluorescein leakage one year after the
initial laser compared to baseline. A secondary outcome will be the change in macular height
as measured (OCT). These outcomes will be assessed for potential use in future trials.
Concerns regarding safety and efficacy follow:
Is the risk of visual loss in patients with clinically significant diabetic macular edema
potentially different across treatment groups?
Preliminary Assessment of Potential Outcomes
Is there evidence that any treatment combinations could be effective in reducing retinal
Is there evidence that Vitamin E may affect the ability of either photocoagulation method to
reduce retinal thickening, or vice versa?
Is there evidence that celecoxib may inhibit retinal thickening?
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 vision and retinal thickness will be compared across three groups; (1)
patients without elevated serum lipids at baseline, (2) patients with elevated lipids at
baseline and receive standard of care treatment, and (3) patients with elevated lipids at
baseline and are aggressively treated pharmacologically.
Patients with type 1 or 2 diabetes.
Patients with clinically significant macular edema in at least one eye.
Best corrected visual acuity 20/400 or better as measured on an ETDRS chart in the eye
with clinically significant macular edema; this eye will be considered the study eye. If
both eyes have clinically significant macular edema and best corrected visual acuity
greater than or equal to 20/400, the right eye will be considered the study eye.
May have had proliferative diabetic retinopathy but scatter photocoagulation must be
performed more than six months ago.
Ocular media sufficiently clear to allow for quality fundus photography.
If Aphakic or pseudophakic, lens removal must have occurred at least 6 months prior to
Clinical diagnosis of diabetes based on any one of the criteria (determined by medical
Documented history of plasma glucose value greater than 210 mg/dl on 3 different
Fasting blood sugar greater than 150 mg/dl on 3 different occasions.
Documented history of ketoacidosis.
Documented history of abnormal glucose tolerance test.
Patient's medical status must include a likelihood of survival for 5
Hemoglobin A1C 12 percent or less.
Willingness to accept randomization for diet or drug therapy for lowering of elevated
Understand and sign the informed consent.
Patients over 18 years of age since the population of interest is primarily older than 18.
A negative urine pregnancy test for women of childbearing potential.
Retinopathy that requires scatter photocoagulation immediately.
Ocular disease other than diabetic retinopathy that may confound the outcome of the study
(e.g. age-related macular degeneration, drug toxicity, uveitis, etc.).
Had previous focal laser photocoagulation for diabetic macular edema.
Poor survival due to other systemic diseases (separate from diabetes)
Poor glycemic control with hemoglobin A1C greater than 12 percent.
Past or current liver disease, which precludes the use of the lipid-lowering drugs.
Vitamin E supplementation over and above the amount in a multivitamin (30 IU/day) one
month prior to entry into the study.
History of hypersensitivity to fluorescein.
History of intra-cranial bleeds.
Evidence of other ocular diseases that may confound the assessment of treatment of
diabetic macular edema.
Prior or current macular detachment in the affected eye(s).
Concurrent celebrex or any other COX-2 inhibitor within 7 days prior to baseline.
Concurrent coumadin therapy or known bleeding diathesis.
Concurrent treatment with a new investigational drug.
Concurrent lithium therapy
Concurrent administration of anti-cholesterol resin medications (e.g. cholestyramine)
Concurrent administration of the anti-obesity drug orlistat (Xenical).
Concurrent administration of other NSAIDs.
Allergy to sulphonomides, NSAIDs, or exhibit the aspirin triad.
Pregnant or lactating women.
Chronic requirement for any ocular medication for other diseases such as glacoma.
Current history of malignancy (except patients 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).